Dr Samples of Two New drugs - FRRVARXABAN and T Prvide

Transcription

1 Implementatin f NICE TA 249 and NICE TA 256 Dabigatran and Rivarxaban fr the preventin f strke and systemic emblism in atrial fibrillatin June

2 Cntents Executive summary Page 3 1. Intrductin Page 4 2. The new ral anticagulants licensed fr strke preventin in AF Page 5 3. Guidance aims and chice f new OAC Page 6 4. Selectin f apprpriate patients Page Pathway fr initiatin Page Shared Care Guidance Page 12 Appendix 1 Page 13 Letter t Primary Care fllwing initiatin f Dabigatran fr Strke Preventin in AF Appendix 2 Page15 Letter t Primary Care fllwing initiatin f Rivarxaban fr Strke Preventin in AF Appendix 3 Page 17 EMA updated Patient and Prescriber infrmatin fr dabigatran 25 th May 2012 Appendix 4 Page 18 EMCVN Generic AF Pathway Guidance authrs Dr Matthew Lyttletn, Cnsultant Haematlgist, Kettering General Hspital Sue Smith, Head f Prescribing and Medicines Management, Nene and Crby Clinical Cmmissining Grups, Nrthamptnshire With cntributins frm - Dr Suchitra Krishnamurthy, Cnsultant Haematlgist, NGH Strke & Care f the Elderly Cnsultants, Cardilgists NGH Sctt Savage, Chief Pharmacist, KGH Dr Jnathan Shribman, GP and primary care East Midlands Cardivascular Netwrk representative Dr Yassir Javaid, GP Nrthamptn Junie Gupta, Frmulary Pharmacist, NGH Prfessr Tm Rbinsn, Strke Lead, East Midlands Cardivascular Netwrk Dr Richard Andrews, Cardiac Lead, East Midlands Cardivascular Netwrk Bayer Behringer Ingelheim Apprved by - Nrthamptnshire Prescribing Advisry Grup 20th June 2012 East Midlands Cardivascular Netwrk June 2012 Review date June

3 Executive summary NICE has issued Technlgy Appraisals fr dabiagtran (Pradaxa ) and fr rivarxaban (Xarelt ) fr the preventin f strke and systemic emblism in atrial fibrillatin (TA 249 and TA 256). This guidance has been prduced t help identify thse patients wh are mst likely t benefit frm dabigatran r rivarxaban and t prvide advice n using these new drugs in the safest pssible manner. The guidance des nt and shuld nt ver-ride the NICE TAs. A clinician may chse t initiate dabigatran r rivarxaban fr any patient within the Technlgy Appraisals criteria if clinically apprpriate. Dabigatran and rivarxaban are rally active antithrmbtic agents. Dabigatran is a direct thrmbin inhibitr and rivarxaban is an ral direct factr Xa inhibitr. Bth drugs have the ptential advantage ver warfarin f nt requiring INR bld mnitring, but ther factrs abut bth drugs need t be taken int cnsideratin when deciding whether either drug is apprpriate fr an individual patient. These factrs include Unknwn lng term safety prfile f the new agents. Bth are black triangle drugs. Lack f reversibility f the new agents. Cnsideratin f the patient s current INR cntrl n warfarin. Renal functin. Bleeding risk, especially GI bleeding risk. Drug interactins Cmpliance. The chice f agent is the decisin f the prescriber and there are prs and cns t each agent. A third new ral anticagulant (OAC), apixaban, is expected t be licensed fr this indicatin later in 2012 and cnsidered by NICE in February Guidance is prvided bth fr patients newly diagnsed with AF and fr existing patients currently taking warfarin. In Nrthamptnshire it is recmmended that bth drugs shuld be initiated nly by a secndary care cnsultant (haematlgist, cardilgist r strke physician as apprpriate) with the supprt f their anticagulant clinics. Prescribing can then be passed t the GP with shared care advice (amber 2 status). This pathway fr initiatin will be reviewed nce experience with these new drugs becmes mre established. Warfarin remains a suitable first-line ral anticagulant fr mst patients

4 1. Intrductin NICE issued a Technlgy Appraisal (TA 249) Dabigatran etexilate fr the preventin f strke and systemic emblism in atrial fibrillatin in March Dabigatran etexilate is recmmended as an ptin fr the preventin f strke and systemic emblism within its licensed indicatin, that is, in peple with nnvalvular atrial fibrillatin with ne r mre f the fllwing risk factrs: previus strke, transient ischaemic attack r systemic emblism left ventricular ejectin fractin belw 40% symptmatic heart failure f New Yrk Heart Assciatin (NYHA) class 2 r abve age 75 years r lder age 65 years r lder with ne f the fllwing: diabetes mellitus, crnary artery disease r hypertensin. 1.2 The decisin abut whether t start treatment with dabigatran etexilate shuld be made after an infrmed discussin between the clinician and the persn abut the risks and benefits f dabigatran etexilate cmpared with warfarin. Fr peple wh are taking warfarin, the ptential risks and benefits f switching t dabigatran etexilate shuld be cnsidered in light f their level f internatinal nrmalised rati (INR) cntrl. NICE issued a Technlgy Appraisal (TA 256) Rivarxaban fr the preventin f strke and systemic emblism in atrial fibrillatin in May Rivarxaban is recmmended as an ptin fr the preventin f strke and systemic emblism within its licensed indicatin, that is, in peple with nnvalvular atrial fibrillatin with ne r mre risk factrs such as: cngestive heart failure hypertensin age 75 years r lder diabetes mellitus, prir strke r transient ischaemic attack. 1.2 The decisin abut whether t start treatment with rivarxaban shuld be made after an infrmed discussin between the clinician and the persn abut the risks and benefits f rivarxaban cmpared with warfarin. Fr peple wh are taking warfarin, the ptential risks and benefits f switching t rivarxaban shuld be cnsidered in light f their level f internatinal nrmalised rati (INR) cntrl. The third new agent, apixaban, anticipates a licence fr this indicatin in late 2012 and a NICE TA is expected in February

5 2. The new ral anticagulants licensed fr strke preventin in AF 2.1 Dabigatran Dabigatran (mre crrectly called dabigatran etexilate a prdrug f dabigatran) is an rally active antithrmbtic agent. It is a direct thrmbin inhibitr, which has the ptential advantage ver warfarin f nt requiring bld mnitring, and may have fewer clinically imprtant drug interactins. The RE-LY study was a Phase III clinical study which evaluated the nn-inferirity f tw dses f dabigatran cmpared with warfarin in peple with AF wh were at mderate t high risk f strke. The primary efficacy endpint f the trial was incidence f strke (including haemrrhagic) and systemic emblism. The primary safety endpint was majr bleeding. The study fund that the lwer dse f dabigatran (110mg bd) was nn-inferir t warfarin at reducing the risk f strke and systemic emblism in peple with AF (RR 0.91; 95% CI 0.74 t 1.11; p<0.001 fr nn-inferirity). The higher dse (150mg bd) was fund t be statistically significantly mre effective than warfarin (RR 0.66; 95%CI 0.53 t 0.82; P<0.001; NNT172 ver ne year). The mean rates fr majr bleeding were 2.71% per year fr lw dse dabigatran, 3.11% per year fr high dse dabigatran and 3.36%/year fr warfarin. Whereas lwdse dabigatran was assciated with a reduced risk f majr bleeding (P=0.003; NNT 154 ver ne year), there were n significant differences between the high-dse dabigatran and warfarin in this respect. Dabigatran has thus demnstrated superirity t warfarin in preventing strkes, particularly haemrrhagic strkes, in peple with AF wh are at mderate r high risk f strkes. This finding, taken tgether with n greater risk f majr bleeding, suggests a pssible rle as an alternative t warfarin in such patients. 2.2 Rivarxaban Rivarxaban is an ral direct factr Xa inhibitr administered as a fixed-dse that des nt require labratry mnitring and, unlike warfarin, has n knwn fd and few drug interactins. The ROCKET AF study was a randmized, duble blind, duble dummy, sham INR trial which cmpared rivarxaban with warfarin. In this study, the per-prtcl, as treated primary analysis was designed t determine whether rivarxaban was nninferir t dse adjusted warfarin (target INR f ) in preventing strke r systemic emblism amnf patients with nn-valvular atrial fibrillatin. Over a median 590 days f treatment expsure in the per-prtcl treatment grup, the event rates fr strke and systemis emblism were 1.7% per year in the rivarxaban daily grup and 2.2% per year in the warfarin grup (HR 0.79; 95% CI 0.66 t 0.96; p< fr nn-inferirity) - 5 -

6 In the intentin t treat (ITT) ppulatin as part f sensitivity analysis, the event rate fr strke and systemic emblism was 2.1% per year fr rivarxaban and 2.4% per year fr warfarin (HR 0.88; 95% CI 0.75 t 1.03; p< fr nn-inferirity and p= 0.12 fr superirity) Clinically relevant bleeding event rate was 14.9% with rivarxaban as against 14.5% per year in the warfarin grup, intracranial haemrrhage ccurred less frequently with rivarxaban (0.5% v/s 0.7% per year; p=0.02) as did fatal bleeding (0.2% v/s 0.5% per year p=0.003) Rivarxaban was thus shwn t be nn-inferir t warfarin in preventing strkes r systemic emblism in peple with atrial fibrillatin wh are at mderate t high risk fr a strke, while demnstrating a cmparable risk f majr and nn majr clinically significant bleeding. Intracranial haemrrhage ccurred less frequently than with warfarin, but the incidence f gastrintestinal bleeding increased. The trial methdlgy increases the cmplexity in interpreting the efficacy data see There are a number f issues raised by bth studies which need t be cnsidered when putting the results in the cntext f nrmal clinical practice. These relate t the level f anticagulant cntrl in the warfarin grups, lng-term safety and tlerability f dabigatran, and limitatins in the study methdlgy. Many f these issues have been cnsidered by NICE. 3. Guidance aims and chice f new OAC This guidance has been prduced t help identify thse patients wh are mst likely t benefit frm dabigatran r rivarxaban and t prvide advice n using these new drugs in the safest pssible manner. The guideline cvers bth newly identified patients and existing patients currently taking warfarin. The guidance des nt and shuld nt ver-ride the NICE TAs. A clinician may initiate dabigatran r rivarxaban fr any patient within the Technlgy Appraisals criteria (as per sectin 1 abve). The guidance is based n the NICE TAs but includes the advice and pinins f lcal clinicians. Additinal guidance t that prvided by the NICE TA is ffered in rder t take int accunt sme f the fllwing issues - In RE-LY, the INR was within the therapeutic range fr 64% f the time. Althugh, this seems lw, this is similar t ther cntemprary trials f warfarin and, in this trial, may reflect the high prprtin f peple in the study wh had nt received warfarin previusly. Nevertheless, sme patients will have been mre cntrlled than thers, and the study des nt address the issue f whether dabigatran wuld be as effective as warfarin in thse peple wh were well cntrlled n warfarin

7 In ROCKET AF, amng patients in the warfarin grup, INR values were within the therapeutic range (2.0 t 3.0) a mean f 55% f the time (median, 58%; interquartile range, 43 t 71). The effect f rivarxaban did nt differ acrss the level f centre TTR. The average TTR at Kettering General hspital is 68% and at NGH it is 71%. The average age f the patients in the RE-LY trial was 71 and in ROCKET AF was 73; the average age f patients taking warfarin in the Nrth Nrthamptnshire ppulatin is 77 and Suth Nrthamptnshire fr females is 73 and males is 71. Sme f these patients may therefre have different risk/ benefit prfiles relating t these drugs than the trial patients. Mre patients discntinued treatment with dabigatran than warfarin during the RE- LY study, which might be due t prer tlerability. A higher incidence f discntinuatins that were a result f serius side effects supprts this view. Annual discntinuatin rates in ROCKET AF were similar between warfarin and rivarxaban (22.2% vs 23.7%). Althugh, majr bleeding was n mre frequent between grups verall, the higher risk f GI side effects (bth dses) and GI bleeding with dabigatran at the 150mg dse cmpared with warfarin raises questins abut its use in peple wh are at high risk f these effects. This was despite the fact that RE-LY excluded patients with a previus GI bleed. Majr bleeding frm a gastrintestinal site was als mre cmmn in the rivarxaban grup than the warfarin grup in ROCKET AF. The best methd fr reversing either dabigatran r rivarxaban is nt knwn. Studies in human vlunteers have shwn that Prthrmbin Cmplex Cncentrate (PCC) can reverse the labratry abnrmalities caused by rivrxaban, but nt dabigatran. Hwever bth drugs are assciated with a nn linear relatinship between prlngatin f cagulatin tests and bleeding tendency and drug levels, and it remains uncertain whether PCC is a clinically effective methd f reversing these drugs. rviia and PCC (Beriplex/Octaplex) have been fund t be ineffective in dabigatran reversal. This may be explained by the fact that dabigatran inhibits the last enzymatic step f the cagulatin cascade. Any agent that replaces cagulatin factrs prximal t thrmbin will nt cmpensate fr the prfund terminal defect in haemstasis. Activated PCC (FEIBA) may imprve haemstasis by prviding small amunts f thrmbin, hwever clinical data t date is lacking. Fr rivarxaban, the high degree f albumin binding in plasma means that it is nt dialysable. All its measurable (labratry) anticagulant effects are reversed by PCC (Beriplex/Octaplex).Clinical data is lacking but it seems reasnable t give a dse f 25IU/kg f PCC in case f acute bleeding. PCC wrks in this setting because it prvides additinal factr II, VII, IX and X and the Xa inhibitr (rivarxaban) is vercme. There are currently n tests t assess the level f anticagulatin (under r ver) being achieved

8 Dabigatran is nt suitable fr patients with CrCl < 30 and requires regular tests f renal functin. Rivarxaban is t be used with cautin in patients with CrCl ml/min A small but significantly greater rate f mycardial infarctin with high-dse dabigatran seen in RE-LY is a signal f ptential lng-term safety which will need t be cnsidered. The abslute differences in this study were small; results suggest that 476 patients, like thse in this study, wuld need t be treated with dabigatran fr ne year fr ne f them t have a mycardial infarctin wh wuld nt have dne if they had received warfarin. This bservatin may reflect a clinical benefit f warfarin rather than an adverse effect f dabigatran. Nevertheless, this raises particular cncerns abut the use f dabigatran in peple wh are at high risk f crnary heart disease. N increase in mycardial infarctins was seen with rivarxaban vs warfarin in ROCKET-AF r any ther studies invlving rivarxaban Lng term safety and tlerability f these new agents is nt yet knwn. Bth are black triangle drugs. Nn-cmpliant patients were excluded frm RE-LY, and they might receive less (if any) benefit frm dabigatran, because the lng half-life f warfarin culd prvide them with a mre cnsistent anticagulant effect. Warfarin cannt usually be put int a Mnitred Dsage System due t the need fr dse adjustments. Dabigatran is unstable after being remved frm the blister pack and is therefre als nt suitable fr administratin using MDS bxes. Rivarxaban may be put int an MDS. The effects f nn-cmpliance with bth dabigatran and rivarxaban might be mre significant because f their shrt half lives cmpared t warfarin

9 In summary the fllwing factrs need t be cnsidered in selecting a new OAC fr SPAF Dabigatran Rivarxaban (Nte that the trials cmpared different levels f INR rates TTR was 64% in RE-LY and 55% in ROCKET AF) Efficacy in strke preventin cmpared t warfarin Reduced risk f bleeding cmpared t warfarin Overall n difference Superir (150mg bd dse) Nn-inferir (110mg bd dse) Evidence fr reduced bleeding risk at lwer dse. NB Increased risk f GI bleed than warfarin at higher dse which is the usual dse. Overall reduced intra cranial haemrrhage (ICH) Overall n difference Nn inferir (ITT analysis) Equivalent t warfarin (except reduced ICH) Reversibility Uncertain. Uncertain (pssible data supprts use PCC which may reverse the labratry abnrmalities f cltting but this may nt translate int stpping the actual bleeding event) Dialysable Yes, but will need t be carried ut fr at least 6 hurs in rder t ensure adequate drug clearance N Dsing bd d Drug interactins P- glycprtein substrates Simultaneus PGP & CYP-3A4 Drug cautins (increased bleeding risk) Antiplatelet agents, NSAIDs, SSRIs r SNRIs Antiplatelet agents, NSAIDs Use in patients with swallwing difficulties Cannt be crushed May be crushed and put thrugh NG tube Suitability fr MDS Nt suitable Suitable Cst / year (Csts may vary in different settings because f negtiated prcurement discunts) Pssibility f using in ther cnditins NICE apprved fr rthpaedic prphylaxis. Phase III data shws efficacy in DVT but n NICE appraisal currently planned NICE apprved fr rthpaedic prphylaxis. Licensed fr treatment f DVT, and the preventin f recurrent DVT and PE fllwing an acute DVT in adults. DVT NICE FAD issued n 1st June Chice f new OAC will need t be reviewed with further data expected in the next mnths, especially regarding reversibility, ther new OACs, and the pprtunity t adpt a single drug acrss a wide variety f indicatins (SPAF, VTE treatment, thrmbprphylaxis) - 9 -

10 4. Selectin f apprpriate patients 4.1 Newly diagnsed AF patients This shuld be used in cnjunctin with the East Midlands Cardivascular Netwrk guideline fr selectin f patients with a CHADS 2 r CHA 2 DS 2 -VASc > r = 2 requiring ral anticagulant strke thrmbprphylaxis. This can be fund at AF Pathway r at appendix 4. Warfarin remains a suitable first-line ral anticagulant fr mst patients Warfarin shuld be the preferred ptin in patients: with egfr < 30 (NB Patients with a baseline egfr f are at risk r prgressive/acute renal dysfunctin and the ptential risks f bleeding with dabigatran r rivarxaban shuld be weighed n an individual basis) with a histry f significant peptic ulcer disease significant ischaemic heart disease in absence f ther determining cnsideratins New OAC may be the preferred ptin in patients: predicted t have variable interacting medicatins e.g. recurrent antibitics with knwn excess use f ethanl wh wuld require dmiciliary testing with high HASBLED scre where dabigatran 110mg bd dsing shuld be cnsidered In all ther patients, wafarin is recmmended as a first line treatment fllwing discussin with patient explaining: lack f lng term data n new OACs issues cncerning reversibility NICE guidance and evidence base n dabigatran / rivarxaban principles used in patient selectin patient will be cnverted t new OAC if TTR < 60% after 4 mnths in presence f cmpliance The NPC decisin aid can be used t explain the risks and benefits t patients. Add weblink when available. 4.2 Existing patients currently taking vitamin K antagnists This shuld be used in cnjunctin with the East Midlands Cardivascular Netwrk guideline fr selectin f patients with a CHADS 2 r CHA 2 DS 2 -VASc > r = 2 requiring ral anticagulant strke thrmbprphylaxis. Warfarin remains a suitable first-line ral anticagulant fr mst patients Cnversin t new OAC will be recmmended fr patients: intlerant f vitamin K antagnists

11 TTR < 60% after > 4 mnths (prviding n evidence nn-cmpliance) Cnversin t new OAC may be cnsidered fr patients: with histry f significant bleed n warfarin (dabigatran 110mg bd preferred) with histry f strke r TIA while taking warfarin (prviding n evidence nn cmpliance) requiring dmiciliary phlebtmy Other patients wh are well cntrlled and tlerant f warfarin are nt recmmended t change. The NPC decisin aid can be used t explain the risks and benefits t patients. Add weblink when available. 5. Pathway fr initiatin 5.1 Newly diagnsed AF patients GP r referring clinician t check FBC U&E cltting screen CHADS 2 / CHA 2 DS 2 VaSc refer t anticagulant department (r cardilgist r strke physician if apprpriate) fr cunselling, inductin and selectin f preferred anticagulant agent If new OAC preferred agent (selectin criteria abve), anticagulant department will: deliver inductin cunselling supply initial 4 week prescriptin enter n acute trust database refer back t Primary Care fr further prescriptins and mnitring Cntent f Inductin Cunseling effect f drug risks (and benefits) f drug risk /benefit f new OAC vs warfarin advice re platelet antagnists Imprtance f cmpliance ntificatin f health prfessinals / use f alert card Management f prcedures infrmatin leaflet including list f knwn drug interactins Patients shuld seek urgent medical attentin if they fall r injure themselves during treatment, especially if they hit their head, due t the increased risk f bleeding

12 5.1.3 When patient is referred frm cardilgy department with planned cardiversin New OAC will be started in cardilgy. There is n data n rivarxaban in cardiversin s dabigatran is strngly preferred. A/C service will see within 5 wrking days t perfrm cunselling, registratin etc (as abve) Patients shuld be reviewed in Cardilgy OP department 4-6 weeks pst cardiversin t cnsider lnger term chice f OAC 5.2 Patients currently taking vitamin K antagnists Anticagulant department t screen database f existing patients fr all patients: with TTR < 60% histry f majr bleeding n warfarin with CHADS 2 r CHA 2 DS 2 VaSc >=1 histry f strke / TIA n warfarin in dmiciliary testing service These patients will be seen in nurse led A/C assessment clinic: t establish cmpliance check U&E t explain ratinale fr cnversin t manage cnversin 1. stp warfarin 2. supply 4 weeks new OAC 3. start new OAC 3 days after discntinuatin (INR t be rechecked until INR <2 if cncerns abut patient) with instructins t be written in Warfarin bk letter t be sent t GP explaining utcme f abve and recmmendatins cncerning mnitring The fllwing patients will be referred frm the nurse led clinic t haematlgy cnsultant led clinic: patients with h/ significant bleeding r high HASBLED uncertainty abut cmpliance 6. Shared Care Guidance 6.1 Infrmatin letter t be supplied t GP 6.2 Recmmended mnitring twice yearly U&E if renal functin nrmal 3 mnthly U&E if renal functin abnrmal annual clinical review t assess risk / benefit 1. h/ strke / TIA 2. check HASBLED including any bleeding episdes with a view t dse reductin r referral back t specialist clinic

13 Appendix 1 Letter t Primary Care fllwing initiatin f Dabigatran fr Strke Preventin in AF Dear Dr Yur patient has tday been started n dabigatran t prevent strke assciated with atrial fibrillatin. The decisin t d s has been made n the basis f: predicted high risk n warfarin (plypharmacy, excess ethanl, high bleeding risk scre) previus pr cntrl n warfarin Time in Treatment Range <60% h/ significant bleeding n warfarin h/ strke r TIA n warfarin CHADS2 HASBLED egfr Yur patient has been prescribed: Dabigatran 150mg bd OR Dabigatran 110mg bd (preferred because f identified high risk f bleeding) Yur patient has been cunselled abut the safe use f dabigatran supplied with the attached infrmatin leaflet supplied with an alert card The fllwing mnitring is recmmended fr patients n dabigatran U&E and FBC Nrmal renal functin 6 mnthly Abnrmal r unstable renal functin 3 mnthly Annual review Histry f any strke / TIA r bleeding in last year recheck HASBLED if HASBLED nw high, r bleeding events, cnsider either reductin t 110 mg bd, r specialist assessment

14 It des nt require INR mnitring It must be stpped if egfr <30 DABIGATRAN KEY POINTS At standard dse (150mg bd) it has the same risk f majr bleeding (but nt intracranial haemrrhage) as warfarin. Dabigatran T1/2 is hurs nly, in presence f nrmal renal functin. Cmpliance is critical therefre, as prtectin frm strke will be lst with missin f nly ne dse (in cntrast t warfarin). In the event f surgery r prcedures, it will be necessary t mit the dse prir t the prcedure See prduct SPCs fr full details f timescales. It interacts with P glycprtein substrates and its use is cntraindicated with: ketcnazle quinidine ciclsprin tacrlimus It shuld be used with cautin with ther p glycprtein substrates e.g verapamil. amidarne, clarithrmycin) with at least 2 hur gap between taking dabigatran and these drugs It causes prlngatin f APTT and TT which are nt hwever measures f degree f anticagulatin. A nrmal Thrmbin time will rule ut the presence f any significant anticagulant effect frm dabigatran There is n established methd acutely t reverse the effect f dabigatran. In the event f suspected verdse, activated charcal shuld be administered within 2 hurs f ingestin. Fr further infrmatin r advice, please cntact the KGH Anticagulant service n bleep 541 r the NGH Anticagulant service n

15 Appendix 2 Letter t Primary Care fllwing initiatin f Rivarxaban fr Strke preventin in AF Dear Dr Yur patient has tday been started n rivarxaban t prevent strke assciated with atrial fibrillatin The decisin t d s has been made n the basis f: Predicted high risk n warfarin (plypharmacy, excess ethanl, high bleeding scre) Previus pr cntrl n warfarin Time in treatment range <60% H/ significant bleeding n warfarin H/ strke r TIA n warfarin CHADS2 HASBLED egfr Yur patient has been prescribed: Yur patient: Rivarxaban 20mg d Has been cunseled abut the safe use f rivarxaban Supplied with the attached infrmatin leaflet Supplied with an alert card The fllwing mnitring is recmmended* fr patients n rivarxaban Annual review Base line FBC, renal functin, LFTs and cltting Renal functin and LFTs mnthly fr first 3 mnths then 3 mnthly Histry f any strke/ TIA r bleeding in the last year Recheck HASBLED and egfr If HASBLED nw high, r bleeding events r egfr between 15-30ml/min, dse f Rivarxaban shuld be reduced t 15mg d r refer fr specialist assessment *lcal recmmendatin; nt in SPC

16 It des nt require INR mnitring RIVAROXABAN KEY POINTS If egfr <15 rivarxaban must nt be initiated and if already initiated, must be stpped In patients with hepatic disease assciated with cagulpathy and clinically significant bleeding risk, including cirrhtic patients rivarxaban shuld nt be prescribed Rivarxaban has a T1/2 f 5-9 hurs in yung patients and hurs in elderly patients s cmpliance is crucial In the event f surgery r prcedures, rivarxaban shuld be stpped 24 hurs prir t the interventin. It interacts with the fllwing drugs: Azle antifungals: Ketcnazle, Vricnazle, Itracnazle, Psacnazle HIV prtease inhibitrs Rifampicin Phenytin, Carbamazepine, Phenbarbital St.Jhn s wrt Rivarxaban causes an increase principally in PT, but this is nt a measure f degree f anticagulatin There is n established methd acutely t reverse the effect f rivarxaban. Fr further infrmatin r advice please cntact the KGH Anticagulant service n bleep 541 r NGH Anticagulant service n

17 Appendix 3 On 25 th May 2012 the Eurpean Medicines Agency updated the Patient and Prescriber infrmatin fr dabigatran (Pradaxa ). This includes updated advice fr patients and prescribers Patients shuld seek urgent medical attentin if they fall r injure themselves during treatment, especially if they hit their head, due t the increased risk f bleeding. Patients taking ther anticagulants (medicines t prevent bld cltting) must nt take Pradaxa except during a perid where their treatment is being switched t r frm Pradaxa. Prescribers are reminded f the need t fllw all the necessary precautins with regard t the risk f bleeding with Pradaxa, including the assessment f kidney functin befre treatment in all patients and during treatment if a deteriratin is suspected, as well as dse reductins in certain patients. Pradaxa must nt be used in patients with a lesin r cnditin putting them at significant risk f majr bleeding (see the revised prduct infrmatin fr details). Pradaxa must nt be used in patients using any ther anticagulant, unless the patient is being switched t r frm Pradaxa (see the revised prduct infrmatin fr details). A Eurpean Cmmissin decisin n this pinin will be issued in due curse

18 Appendix 4

19