Real-world outcomes of anti-vegf treatment for retinal vein occlusion in Portugal

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1 EJO ISSN Eur J Ophthlmol 2017; 00 (00): DOI: /ejo ORIGINAL RESEARCH ARTICLE Rel-world outcomes of nti-vegf tretment for retinl vein occlusion in Portugl Sr Vz-Pereir 1,2, Inês P. Mrques 3, João Mtis 4, Filipe Mir 5, Lígi Rieiro 6, Rit Flores 7,8 ; on ehlf of the Portuguese Multicenter Study Group of Retinl Vsculr Diseses (PORTUGAL)* 1 Deprtment of Ophthlmology, Hospitl de Snt Mri, Centro Hospitlr Liso Norte, Lison - Portugl 2 Deprtment of Ophthlmology, Fculty of Medicine, Universidde de Liso, Lison - Portugl 3 AIBILI Assocition for Innovtion nd Biomedicl Reserch on Light nd Imge, Coimr - Portugl 4 Deprtment of Ophthlmology, Centro Hospitlr do Bixo Voug, Aveiro - Portugl 5 Deprtment of Ophthlmology, Centro Hospitlr Médio Tejo, EPE, Torres Novs - Portugl 6 Deprtment of Ophthlmology, Centro Hospitlr Vil Nov de Gi e Espinho, Vil Nov de Gi - Portugl 7 Deprtment of Ophthlmology, Centro Hospitlr de Liso Centrl, Lison - Portugl 8 Deprtment of Ophthlmology, Nov Medicl School, Lison - Portugl * Memers of the Portuguese Mutlicenter Study Group of Retinl Vsculr Diseses (PORTUGAL) re listed in the Appendix Astrct Purpose: Retinl vein occlusion (RVO) is n importnt cuse of visul disility in the modern world. We im to evlute the rel-world outcomes of ptients with RVO treted with nti-vsculr endothelil growth fctor (VEGF) in Portugl. Methods: We performed retrospective, oservtionl, multicenter study including 8 centers cross Portugl nd 200 ptients treted with either rniizum or evcizum. Dt were collected t 3 time points: time of dignosis (0 time point) nd 6 nd 12 months fter inititing tretment. Demogrphic nd clinicl dt were collected. Results: Medin visul cuity (VA) nd centrl mculr thickness (CMT) improved in the rnch RVO (BRVO), centrl RVO (CRVO), evcizum, nd rniizum groups t 6 nd 12 months compred to seline, with CMT improving further only in the CRVO nd rniizum groups etween 6 nd 12 months (p = nd p = 0.001, respectively). The CMT ws lower in the rniizum group compred to the evcizum group oth t 6 nd 12 months (p<0.02). Medin CMT improved in oth the good nd poor seline VA groups t 6 nd 12 months compred to seline (p<0.001). Medin VA only improved for the group with poor seline VA t 6 nd 12 months of follow-up (p<0.001). Regression nlysis identified severl seline vriles s predictors of visul outcomes t 6 nd 12 months, with different results depending on the nlyzed group. Conclusions: Both tretments were effective, lthough less effective thn results reported in clinicl trils. The morphologic response ws etter with rniizum compred to evcizum, lthough functionlly there were no differences. Keywords: Anti-VEGF, Retinl vein occlusion, Visul prognosis Introduction Retinl vein occlusions (RVO) re the second most frequent retinl vsculopthy fter dietic retinopthy. Retinl vein occlusions hve glol ge- nd sex-stndrdized prev- Accepted: Jnury 29, 2017 Pulished online: Ferury 28, 2017 Corresponding uthor: Rit Flores, MD Deprtment of Ophthlmology Hospitl de Snto António dos Cpuchos Centro Hospitlr de Liso Centrl Almed de Snto António dos Cpuchos Lison, Portugl ritmriflores@gmil.com lence of 5.20 per 1,000: 4.42 per 1,000 nd 0.80 per 1,000 for rnch RVO (BRVO) nd centrl RVO (CRVO), respectively. It is estimted tht 16.4 million dults re ffected y RVO worldwide, corresponding to 13.9 million with BRVO nd 2.5 million with CRVO (1). The clssifiction of RVO into BRVO nd CRVO is sed on the ntomicl site of the vsculr occlusion. Although the pthogenesis of RVO is not yet fully understood, n incresed secretion of the vsculr endothelil growth fctor (VEGF) is oserved, nd therefore the use of nti-vegf gents y intrvitrel injections hs ecome common (2). Mny tretment regimens hve een suggested with nti-vegf gents, such s monthly injections or injections pro re nt (PRN), ut the idel regimen hs not een defined (2) nd mngement in the long-term of RVO-relted complictions nd visul loss hs not een estlished (1).

2 2 Anti-VEGF for ME secondry to RVO Among other therpeutic indictions, rniizum nd fliercept re pproved y the Food nd Drug Administrtion nd Europen Medicines Agency for the tretment of visul impirment due to mculr edem secondry to BRVO or CRVO (2-4), while evcizum is used off-lel worldwide (2, 5, 6) if rniizum or fliercept re unville or due to economic considertions (6). It is of the utmost importnce to understnd how ptients with RVO re eing treted in rel-world setting, outside clinicl trils, in order to identify mesures tht cn e implemented to improve the visul outcomes of these ptients. The im of this study ws to chrcterize, in rel-world setting, ptients with RVO treted with nti-vegf in Portugl, nd evlute the respective functionl nd ntomicl outcomes. Methods Study design This retrospective, oservtionl, multicenter study included 8 centers cross Portugl. Prticipnts nd inclusion nd exclusion criteri Files from ptients with RVO were retrospectively reviewed etween Jnury nd Decemer Inclusion criteri were ge 18 yers or older, dignosis of CRVO or BRVO with centrl mculr edem, nti-vegf s primry tretment (rniizum or evcizum), nd follow-up of t lest 12 months. Exclusion criteri included mculr edem secondry to cuses other thn RVO (e.g., ge-relted mculr degenertion, dietic retinopthy, centrl serous retinopthy, uveitis), previous mculr lser photocogultion, previous nti-vegf tretment due to conditions other thn RVO, previous intrvitrel or su-tenon corticosteroid injection, nd history of vitreoretinl surgery. This study ws conducted ccording to the tenets of the Declrtion of Helsinki. All prticipnts provided written informed consent. Dt collection Dt were collected t 3 time points: t the time of dignosis (0 time point) nd 6 nd 12 months fter inititing tretment. Clinicl nd demogrphic dt collected included ge, sex, type of RVO (CRVO or BRVO), comoridities, est-corrected visul cuity (BCVA), centrl mculr thickness (CMT), nd phkic sttus. Tretment dt included numer of injections, type of nti-vegf used, time to tretment, nd djuvnt lser or corticosteroid therpy. Sttisticl nlysis After ssessing the normlity of ll vriles using the Kolmogorov-Smirnov test, nonprmetric sttistics methods were used. For sttisticl purposes, Snellen frctions were converted to the logrithm of the minimum ngle of resolution (logmar) y stndrd conversion method (7). Dt were nlyzed considering ll ptients nd 6 sugroups: CRVO or BRVO, rniizum or evcizum tretment, nd good or poor seline visul cuity, defined s logmar 0.30 nd logmar 1.00, respectively. Between-group nlysis ws performed using the Mnn-Whitney U test or the χ 2 test, respectively, for continuous nd discrete vriles. Within-group nlysis ws performed using the Friedmn or Wilcoxon test, s pproprite. Explortory univrite nlyses were performed, followed y multivrite regression nlyses to determine predictors of BCVA nd CMT t 6 nd 12 months, depending on the 6 studied sugroups. The vriles selected for the multivrite nlyses were those found to e sttisticlly significnt from the univrite nlyses s well s cliniclly relevnt. The Bonferroni correction ws pplied to oth univrite nd multivrite nlyses s needed. Tests were considered significnt t α = 0.05 significnce level (2-sided). Results A totl of 200 eyes from 200 ptients with centrl mculr edem secondry to RVO were included in this study. There were 124 eyes with BRVO nd 76 eyes with CRVO. Study popultion nd seline vlues Bseline demogrphics nd clinicl chrcteristics ccording to type of RVO nd for the totl popultion smple re shown in Tle I. There were no significnt differences etween the studied vriles when compring ptients with BRVO or CRVO, except for CMT, which ws higher for ptients with CRVO (p<0.001). There were no differences etween groups concerning seline BCVA or ge. Best-corrected visul cuity nd CMT over the 12-month study period ccording to type of RVO Anlysis of the 3 time points seline, 6 months, nd 12 months showed tht the medin BCVA improved in oth the BRVO nd CRVO groups t 6 nd 12 months compred to seline (p<0.01), from 0.70 to 0.43 nd 0.44 nd from 0.80 to 0.70 nd 0.70, respectively. No differences were found etween 6 nd 12 months of follow-up. Between-group nlysis showed tht, t oth 6 nd 12 months, medin BCVA ws etter in the BRVO group (p<0.005). Medin CMT decresed in oth the BRVO nd CRVO groups t 6 nd 12 months compred to seline, ut only the CRVO group showed sttisticlly significnt decrese, lso etween 6 nd 12 months (p<0.001 nd p = 0.002, respectively). Between-group nlysis reveled tht, t oth seline nd 6 months, medin CMT ws lower in the BRVO group (p<0.005), with no differences t 12 months (T. II). Best-corrected visul cuity nd CMT over the 12-month study period ccording to tretment Anlysis of the 3 time points seline, 6 months, nd 12 months showed tht the medin BCVA improved in oth the rniizum nd evcizum groups t 6 nd 12 months

3 Vz-Pereir et l 3 TABLE I - Bseline demogrphics nd clinicl chrcteristics ccording to type of retinl vein occlusion nd for the totl popultion smple Prmeter BRVO CRVO Totl No. (%) 124 (62.0) 76 (38.0) 200 (100.0) Age, y, medin (min-mx) 70.0 ( ) 69.5 ( ) 70.0 ( ) Femle, % Rniizum, n (%) 65 (52.4) 42 (55.3) 107 (53.3) BCVA, logmar, medin (min-mx) 0.70 ( ) 0.80 ( ) 0.70 ( ) CMT, µm, medin (min-mx) ( ) ( ) ( ) LogMAR 0.30, % LogMAR 1.00, % Crdiovsculr comoridities, % Glucom Pseudophkic, % p< Hypertension + type 2 dietes mellitus. BCVA = est-corrected visul cuity; BRVO = rnch retinl vein occlusion; CMT = centrl mculr thickness; CRVO = centrl retinl vein occlusion; logmar 0.30 = good vision t seline; logmar 1.00 = poor vision t seline. TABLE II - Best-corrected visul cuity (BCVA) nd centrl mculr thickness (CMT) in ptients with rnch retinl vein occlusion (BRVO) nd ptients with centrl retinl vein occlusion (CRVO) Prmeter Bseline 6 months 12 months BCVA, logmar BRVO 0.70 (0.60) 0.43 (0.45) 0.44 (0.50) CRVO 0.80 (0.80) 0.70 (0.79) 0.70 (0.90) CMT, µm c BRVO (257.0) (145.0) (148.0) CRVO (289.0) (378.0),d (221.0) d p<0.01 Within groups, for differences etween seline nd 6 months nd seline nd 12 months. p<0.005 Between groups. c p<0.001 Within groups, for differences etween seline nd 6 months nd seline nd 12 months. d p = All vlues presented s medin (interqurtile rnge). TABLE III - Best-corrected visul cuity (BCVA) nd centrl mculr thickness (CMT) over the 12-month study period ccording to tretment Prmeter Bseline 6 months 12 months Rniizum, BCVA, logmar 0.70 ( ) 0.50 (-0.10 to 1.68) 0.50 ( ) CMT, µm ( ,430.0) c ( ,161.0) c ( ,489.0) Bevcizum BCVA, logmar 0.80 ( ) 0.60 ( ) 0.55 ( ) CMT, µm ( ,306.0) c ( ,130.0) c ( ,308.0) p<0.001 Within groups, for differences etween seline nd 6 months nd seline nd 12 months for oth BCVA nd CMT. p = Within group, for CMT difference etween 6 nd 12 months. c p<0.02 Between groups. All vlues presented s medin (minimum-mximum). compred to seline (p<0.001), from 0.70 to 0.50 nd 0.50 nd from 0.80 to 0.60 nd 0.55, respectively, with no difference etween 6 nd 12 months. There were no significnt differences etween groups in the BCVA prmeter t oth 6 nd 12 months. Medin CMT decresed in oth the rniizum nd evcizum groups t 6 nd 12 months compred to seline, ut only the rniizum group showed sttisticlly significnt decrese, lso etween 6 nd 12 months (p<0.001 nd p<0.001, respectively). Between-group nlysis reveled tht, t oth 6 nd 12 months, medin CMT ws lower in the rniizum group (p<0.02) (T. III). Also, more ptients in the evcizum group underwent rescue grid lser photocogultion during follow-up (66.3% vs 29.9%, p<0.001). Best-corrected visul cuity nd CMT over the 12-month study period ccording to BCVA t seline Medin CMT improved in oth groups t 6 nd 12 months compred to seline (p<0.001), with further decrese etween 6 nd 12 months for the group with poor vision t seline (p = 0.012). Medin BCVA only improved in the poor vision group t 6 nd 12 months compred to seline (p<0.001), with no difference etween 6 nd 12 months, from 1.30 to 0.90 nd 0.89, respectively (T. IV). Concerning seline chrcteristics, the group with good visul cuity t seline ws younger compred to the group with poor visul cuity, with medin (minimum-mximum) ge of 63.0 (33.0-

4 4 Anti-VEGF for ME secondry to RVO TABLE IV - Best-corrected visul cuity (BCVA) nd centrl mculr thickness (CMT) over the 12-month study period ccording to BCVA t seline Prmeter Bseline 6 months 12 months LogMAR 0.30 BCVA, logmar 0.30 ( ) 0.20 (-0.10 to 0.70) 0.14 ( ) CMT, µm ( ) ( ) ( ) LogMAR 1.00 BCVA, logmar 1.30 ( ) 0.90 ( ) 0.89 ( ) CMT, µm c ( ,430.0) ( ,161.0) ( ,489.0) p<0.001 Between groups. p<0.001 Within group, for differences etween seline nd 6 months nd seline nd 12 months. c p<0.001 Within group, for difference etween seline nd 6 nd 12 months, with p = for difference etween 6 nd 12 months. LogMAR 0.30 = good vision t seline; logmar 1.00 = poor vision t seline. All vlues presented s medin (minimum-mximum). TABLE V - Predictors of est-corrected visul cuity (BCVA) nd centrl mculr thickness t 6 nd 12 months, depending on the 6 studied sugroups Sugroup/ predictor(s) BCVA (logmar) 6 months BCVA (logmar) 12 months CMT (µm) 6 months CMT (µm) 12 months B 95% CI p B 95% CI p B 95% CI p B 95% CI p CRVO BCVA seline < <0.001 BRVO BCVA seline < <0.001 No. injections to <0.001 first 6 months Age <0.001 Rniizum BCVA seline < <0.001 Age <0.001 Bevcizum BCVA seline < <0.001 Age LogMAR 0.30 TDT, mo < % CI = 95% confidence intervl for B; B = unstndrdized coefficient; BRVO = rnch retinl vein occlusion; CRVO = centrl retinl vein occlusion; logmar 0.30 = good vision t seline; logmar 1.00 = poor vision t seline; TDT = time from dignosis to tretment. 86.0) vs 70.0 ( ) yers (p = 0.016). More ptients in the poor vision group underwent rescue grid lser photocogultion during follow-up (54.4% vs 32.4%, p = 0.040). Numer of injections during the 12-month study period The medin numer of injections ws the sme for the BRVO nd the CRVO groups, oth during the first 6 months (medin of 3 injections) nd from 6 to 12 months (medin of 1 injection). The medin (minimum-mximum) totl numer of injections for the BRVO group ws 4 (1-11) nd for the CRVO group 4 (1-12), which ws not sttisticlly different. The medin (minimum-mximum) numer of injections during the first 6 months, from 6 to 12 months, nd totl numer of injections ws 3 (0-6), 1 (0-5), nd 4 (1-10) in the rniizum group nd 3 (0-7), 1 (0-4), nd 4 (1-10) in the evcizum group (p>0.05). No significnt differences were seen etween the groups with good nd poor vision t seline, with the medin (minimummximum) numer of injections during the first 6 months, from 6 to 12 months, nd totl numer of injections eing 2.5 (0-6), 1 (0-5), nd 3.5 (1-11) for the good vision group nd 3 (0-7), 1 (0-4), nd 4 (1-10) for the poor vision group. Regression nlyses Significnt results from the univrite nd multivrite regression nlyses to determine predictors of BCVA nd CMT t 6 nd 12 months, depending on 5 of the 6 studied sugroups, re presented in Tle V. There were no identified predictors for the group with poor seline vision. A worse BCVA t seline ws predictor of worse BCVA t 6 nd 12 months for ll groups (p<0.001), except for the group with

5 Vz-Pereir et l 5 good vision t seline. For this group, only shorter time from dignosis to tretment ws predictor of etter BCVA nd CMT, oth t 6 nd 12 months (p = nd p = t 6 months, p<0.001 nd p = t 12 months). Older ge ws predictor of worse BCVA t 12 months in the BRVO nd evcizum groups (p<0.001 nd p = 0.017, respectively), while in the rniizum group it ws predictor of worse BCVA t oth 6 nd 12 months (p = nd p<0.001, respectively). Only in the BRVO group ws lower numer of injections during the first 6 months of tretment predictor of worse BCVA t 6 months (p<0.001). Discussion Our results showed tht, regrdless of tretment or seline visul cuity, medin BCVA nd CMT improved in oth the BRVO nd CRVO groups t 6 nd 12 months compred to seline. However, while there ws no difference in BCVA etween 6 nd 12 months, the CRVO group continued to show sttisticlly significnt decrese in CMT in this period. Since this CMT reduction ws not ccompnied y BCVA chnge, we my speculte tht the structurl result etter reflected the effect of tretment thn the functionl result. Brynskov et l (8) reported tht, in CRVO, the functionl outcome did not mirror the ntomicl outcome, nd Pielen et l, in the Rniizum for Brnch Retinl Vein Occlusion Associted Mculr Edem Study (RABAMES) (9), showed tht, in BRVO, centrl retinl thickness incresed slowly fter stopping injections, wheres improvement in visul cuity ws sustined, indicting tht morphologic chnges occur prior to functionl impirment (9). In our CRVO popultion, functionl nd structurl improvement occurred simultneously until 6 months of follow-up, ut fter this period only morphologic improvement continued to occur. This my e explined y the durtion of the edem nd susequent photoreceptor dmge, which could limit complete visul cuity recovery. When compring the CRVO group with the BRVO group, medin BCVA ws etter in the BRVO group oth t 6 nd 12 months, nd medin CMT ws lower t oth seline nd 6 months in the sme group. Our study popultion received medin of 3 injections in the first 6 months (evcizum or rniizum) nd 1 injection etween 6 nd 12 months in oth groups. When compring evcizum vs rniizum, our results showed tht, lthough they were oth effective in reducing BCVA nd CMT in the first 6 months, only rniizum further reduced CMT etween months 6 nd 12. Moreover, CMT ws lower in the rniizum group when compred to the evcizum group, oth t 6 nd 12 months, with no differences in BCVA etween groups. The medin numer of injections ws similr etween the rniizum nd evcizum groups, with 3 injections during the first 6 months nd 1 injection from 6 to 12 months. Our results re in line with other rel-world studies, which hve shown tht, in ptients with RVO, nd s erly s t 2 weeks postinjection, CMT reduction is higher with rniizum compred to evcizum (10). Two prospective trils compring evcizum nd rniizum in the tretment of RVO (11) or BRVO (12) concluded tht oth gents hd similr effects in reducing mculr thickness nd improving visul cuity t 6 months (11), even using PRN regimen, with men numer of injections of evcizum nd rniizum of 3.2 nd 3.0, respectively (12). Therefore, oth evcizum nd rniizum re effective, even with rel-world tretment regimens using lower numer of injections thn recommended. Our results lso showed tht more ptients in the evcizum group underwent rescue grid lser photocogultion during follow-up (66.3% vs 29.9%, p<0.001). Other studies reported rescue grid lser tretment of 51% (13) nd 42% (14) for BRVO nd 16.5% (14) for CRVO fter evcizum therpy, ut there re no studies directly compring evcizum with rniizum. In our popultion smple, rniizum seemed to prevent the need for rescue lser tretment more efficiently thn evcizum, ut this result hs to e confirmed. One study reported tht, in ptients with BRVO treted with rniizum, ptients with worse seline visul cuity showed greter visul enefit from tretment (15). Our results re in ccordnce with this study, since only the group with poor vision t seline hd further decresed CMT etween 6 nd 12 months nd improved medin BCVA t 6 nd 12 months compred to seline. This my reflect the worse condition of these ptients, which, unlike the good vision group, could still improve, s ws the cse with the CRVO group. These results support our previous suggestion tht the structurl result etter reflects the effect of tretment thn the functionl result. The group with poor visul cuity t seline ws older nd more ptients in this group underwent rescue grid lser photocogultion during follow-up. We did not identify ny predictors of the studied outcomes for the group with poor seline vision. We my speculte tht these ptients hd such serious condition tht ll efforts to improve their sttus re independent of the predictor vriles identified for the other groups. For the other 5 nlyzed groups, worse BCVA t seline ws predictor of worse BCVA t 6 nd 12 months for ll groups, except for the group with good seline vision, proly ecuse these ptients hd smller mrgin for improvement. Other studies hve reported similr results (16-20). Older ge ws predictor of worse BCVA in the BRVO, evcizum, nd rniizum groups, which is in greement with other reports (8, 16-20). Only in the BRVO group ws lower numer of injections during the first 6 months of tretment predictor of worse BCVA t 6 months. This result suggests tht these ptients re eing undertreted nd could hve improved outcomes with more intensive pproch during the first 6 months of tretment. Severl studies hve reported erly tretment s predictor of etter visul outcomes (17, 21-25) for oth BRVO nd CRVO. Our results show tht shorter time from dignosis to tretment is only predictor of etter BCVA nd CMT, oth t 6 nd 12 months, in the group with good vision t seline. This suggests tht the therpy should e dministered s soon s possile fter the dignosis. In summry, oth tretments were effective, lthough less effective thn results reported in clinicl trils. Most ptients were treted using PRN regimen nd experienced the constrints of the pulic helth cre system nd overooked gends. It is thus not surprising tht rel-world ptients re undertreted.

6 6 Anti-VEGF for ME secondry to RVO Appendix Memers of the Portuguese Multicenter Study Group of Retinl Vsculr Diseses (PORTUGAL): André Diogo Brt (Deprtment of Ophthlmology, Hospitl de Snt Mri, Centro Hospitlr Liso Norte, Lison; Deprtment of Ophthlmology, Fculty of Medicine, Universidde de Liso, Lison), Bárr Borges (Deprtment of Ophthlmology, Centro Hospitlr Liso Centrl, Lison), An Cugueir (Deprtment of Ophthlmology, Centro Hospitlr Liso Centrl, Lison), Jon Cmpos (Deprtment of Ophthlmology, Centro Hospitlr de Leiri, Leiri), Rit Mtos (Deprtment of Ophthlmology, Centro Hospitlr do Bixo Voug, Aveiro), Filipe S. Neves (Deprtment of Ophthlmology, Centro Hospitlr Vil Nov de Gi e Espinho, Vil Nov de Gi), nd Miguel Ruão (Deprtment of Ophthlmology, Centro Hospitlr de Entre o Douro e Voug, Snt Mri d Feir). Disclosures Finncil support: Dr. Vz-Pereir reports personl fees nd nonfinncil support from Byer nd nonfinncil support from Allergn nd Novrtis, outside the sumitted work. Dr. Flores reports personl fees nd nonfinncil support from Allergn nd Byer nd nonfinncil support from Novrtis, outside the sumitted work. Conflict of interest: None of the uthors hs conflict of interest with this sumission. Meeting presenttion: This work ws presented s poster t the 1 st scientific meeting of the Portuguese Retin Study Group (GER), Lison, Ferury 13, 2016; s poster t the 16 th ESASO Retin Acdemy, Estoril, Portugl, June 23-25, 2016; nd s presenttion t the 16 th EURETINA Congress, Copenhgen, Septemer 8-11, References 1. Ho M, Liu DT, Lm DS, Jons JB. Retinl vein occlusions, from sics to the ltest tretment. Retin. 2016;36(3): Cmp C, Alivernini G, Bollett E, Prodi MB, Perri P. Anti-VEGF Therpy for Retinl Vein Occlusions. Curr Drug Trgets. 2016;17(3): Europen Medicines Agency wesite. Authoriztion detils of Lucentis (rniizum). curl=pges/medicines/humn/medicines/000715/humn_med_ jsp&mid=WC001c058001d124. Accessed Decemer 14, Europen Medicines Agency wesite. 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