council recommend februari test relat place market proprietari medicin product eec council european commun regard treati establish european econom commun regard propos commi sion regard opinion european parliament regard opinion econom social committe council recommend eec test relat place market proprietari medicin product council adopt seri note guidanc intend prevent differ interpret conduct evalu test proprietari medicin product provid council direct eec approxim law member state relat analyt pharmaco toxicolog clinic standard protocol respect test proprietari medicin product amend direct eec adopt note guidanc supplement annex recommend eec promot free movement proprietari medicin product facilit take consider member state market author grant member state pharmaceut committe committe proprietari medicin product consult measur contain recommend recommend member state seek ensur conduct test present result applic author place proprietari medicin product market compli principl adher methodolog set note guidanc annex hereto examin evalu accord note guidanc applic market author brussel februari council presid de keersmaek oj oj oj oj oj oj annex singl dose toxic note guidanc applic annex direct eec part chapter view grant market author drug quot quot introduct guidelin deal qualit quantit studi toxic phenomena occurr relat time singl administr substanc combin stanc studi give indic effect acut overdosag man design toxic studi requir repeat dose relev anim speci singl dose toxic test conduct sign acut toxic reveal mode death determin suitabl speci quantit evalu approxim lethal dose inform dose effect relationship made high level precis requir toxicologist judgement design studi maxim amount relev inform obtain smallest number anim quot quot product specif drug substanc activ substanc pattern impur product market final dosag form shown impur significantli quantiti qualiti test batch step ascertain toxic consider physic characterist drug substanc relat rout administr particl size compound oral finish product larg anim acut toxic studi conduct studi pharmaceut formul intend market desir pharmaceut formul lead major bioavail activ ingredi excipi excipi time evalu activ substanc product combin activ substanc case combin activ substanc make studi activ substanc separ combin activ substanc proport propos final product order check enhanc toxic toxic effect occur deviat protocol depend document pharmacokinet pharmacodynam differ anim speci studi man degrad product degrad product occur condit storag consider toxic evalu initi acut toxic studi quot quot anim singl dose toxic test conduct mammalian speci strain equal number sex rodent mous rat hamster suitabl qualit studi toxic sign quantit determin approxim lethal dose differ respons observ anim sex rodent speci anim sex acut toxic studi toxic sign observ record detail anim case mammal speci strain anim select essenti inform provid ag sex weight origin time laboratori test anim classifi free specif pathogen anim vaccin submit procedur detail hous environment condit access natur diet avail water state factor affect acut toxic stanc quot quot administr rout administrationin case rodent gener rout includ rout propos man ensur full access unchang drug circul propos rout administr man intraven rout anim test accept condit administr detail administr product provid includ particular vehicl adjuvan method prepar suspens case insolubl product concentr solut volum administ rout method administr formul administ bland close physiolog ph osmol special attent paid formul alkalin acid potenti corros exceed toler volum avoid intraven rout rate infus ml min ph temperatur solut administ pro vide inject site parenter administr state dose level speci number dose level spectrum toxic reveal rodent quantit estim approxim lethal dose effect relationship obtain quot quot observ anim observ regular interv sign toxic time occurr sever durat progress record time mode death document sign toxic present separ anim observ dai continu long sign toxic appar progress loss weight inhibit growth quot quot autopsi anim surviv end studi anim dy period observ subject autopsi organ show macroscop agon subject histopatholog examin document adequ explan basi previou experi strain anim quot quot present data result calcul made detail method calcul state toxid effect includ assess morbid speci rout administr dose level investig draw relev conclus data obtain studi signific deviat guidelin justifi annex ii test medicin product mutagen potenti quot quot introduct mutagenesi refer genet materi individu cell brought spontan chemic physic mean successor differ perman herit predecessor current scientif knowledg overwhelmingli support concept chemic possess mutagen properti present potenti genet hazard futur gener potenti cancer risk present necess identifi chemic properti limit human exposur posit evid mutagen consider evalu risk carcinogen direct eec primari object guidelin determin exist mutagen hazard damag genet apparatu level individu gene point mutat interfer grosser type structur chromosom chromosom mutat number genom mutat alter structur alter small result delet gene net effect difficult distinguish point mutat wide varieti procedur devis test abil chemic induc kind mutat organ rang simplest arrang deoxyribonucl acid molecul dna bacteria prokaryot dna arrang complex associ protein enzym system chromatin form chromosom system found eukaryot rang simpl organ fungi insect final mammal quot quot object mutagen test procedur direct eec state substanc medicin product prior market investig mutagen properti object note provid guidanc conduct investig design mutagen test procedur point primari import procedur identifi chemic mutagen properti maximum accuraci reason cost wide varieti test deliber choic made procedur capabl detect main class relev genet damag notabl gene mutat chromosom mutat genom mutat procedur account fact dna univers prokaryot eukaryot organ genet materi type organ capac metabol xenobiot compound differ wide organ test system vitro procedur mammalian metabol simul addit extrins metabol activ system fail mimic vivo situat critic point includ vivo test test characterist metabol substanc account quot quot propos mutagen test medicin product gener acknowledg requir consider met singl test select combin procedur combin test appli case depend specif characterist substanc test base current knowledg system categori test propos approach meet condit set paragraph impli test inappropri evid test accept altern part packag deviat procedur instanc characterist compound studi featur metabol consid inappropri evalu potent antibacteri agent abacteri test convers toxic studi reveal effect reproduct system germ cell event respons applic justifi reason select individu test explain strategi system test chosen test categori select test gene mutat bacteria wide test assess mutagen properti chemic test carri establish bacteri strain design detect type genet chang includ frame shift base chang mutat test carri extrins metabol activ test chromosom aberr mammalian cell vitro procedur human lymphocyt mammalian cell line damag score microscop examin chromosom mitot metaphas test carri extrins metabol activ test gene mutat eukaryot system relev test posit result found bacteria addition studi system complex eukaryot chromosom structur structur complex possibl detect mutat aris mechan occur simpl bacteri genom suitabl test includ mammalian cell design detect induct mutat specif loci code enzym hypoxanthin guanin phosphoribosyl transferas thymidin kinas eukaryot fungi insect consid extrins metabol activ incorpor test vivo test genet damag main role vivo test categori test ascertain mutagen compound miss vitro test inappropri metabol activ system valid test end point chromosom damag bone marrow metaphas micronucleu test domin lethal test vivotest somat gene mutat mous spot test wide test valid conduct line establish procedur set current intern literatur notabl omiss recommend test packag includ test primarili design detect genom mutat disjunct aneuploidi specif method present develop suffici valid incorpor note guidanc prepar light current knowledg expect futur modifi test procedur evolv appli practic order accommod futur develop note guidanc period updat quot quot interpret result object mutagen test procedur establish reason certainti substanc possess mutagen properti separ issu signific obtain result term genet hazard man result convincingli substanc effect test reason conclud possibl mutagen hazard accept low order consid insuffici evid absenc carcinogen potenti result vitro vivo compound mutagen properti argu strongli exist risk human occur situat result uniform expect test design end point characterist metabol activ case signific posit neg result judg number natur instanc packag posit result vivo test deserv weight posit bacteri test differ appli neg result impli neg vivo test necessarili invalid seri posit result obtainedin vitro understand genotox potenti substanc gain carri supplementari investig manufactur decid supplementari test carri select select base result obtain properti compound intend consult regulatori author quot quot risk benefit consider compound shown possess mutagen properti potenti substanc present genet hazard man time constitut risk tumour induct mammalian test herit transloc test specif locu test occasion assess genet risk human test expens requir larg number anim applic justifi found case risk benefit assess mutagen consider result mutagen test pharmacokinet metabol toxic profil addit intend medicin product degre exposur ag reproduct statu patient aspect potenti risk altern substanc consider annex iii cardiac glycosid quot quot gener note design view clinic evalu cardiac glycosid appli drug share pharmacolog action heart posit inotrop neg chronotrop dromotrop effect note guidanc read light norm protocol direct eec intend sole assist applic interpret respect specif problem present cardiac glycosid analog drug manag cardiac diseas clinic practic drug evalu drug situat fraught difficulti result low therapeut toxic dose ratio compound problem respect pharmacokinet tendenc accumul bioavail problem multitud extrins intrins factor influenc therapeut efficaci fact studi drug inevit involv critic ill patient unstabl diseas pattern vari aetiolog quot quot problem aris low therapeut toxic dose ratio gener remarksnot infrequ modest overdos extracardiac symptom toxic evid cardiac toxic addit undertreat difficult defin assai method plasma concentr provid insight relationship pharmacokinet pharmacodynam therapeut toxic effect fulli understood recommend stand problem plasma concentr assai mention assai perform provid valuabl inform unexpect side effect relat toxic concentr drug metabolit receptor site target organ failur treatment link unexpectedli low valu provid quantit inform therapeut toxic plasma concentr ratio correl dose quot quot tendenc accumul gener remark cardiac glycosid commonli character slow tissu uptak extens tissu bind prolong half life long durat action pharmacokinet pharmacodynam factor defin recommend clear evid obtain limit dosag excess accumul avoid clinic pharmacokinet data justifi dosag regimen chronic treatment judg load dose patient drug data time expect elaps start therapi sign clinic effect initi clinic studi effect drug continu longer time obtain steadi state plasma level durat basic investig depend pharmacokinet individu glycosid addit drug long term efficaci advers effect clinic evid accumul studi longer period studi evid exclud risk accumul sought clinic factor list paragraph profoundli alter pharmacokinet behaviour drug account analyz data quot quot problem relat bioavail gener remark slight differ pharmaceut formul result mark variat plasma concentr individu due differ rate extent absorpt cardiac glycosid oral absorpt view narrow therapeut index variat plasma concentr hazard shown factor paramount import cardiac glycosid degre bioavail vari approxim oral ouabain case digitoxin encount clinic practic individu intersubject variat plasma concentr increas bioavail decreas oral absorpt depend pharmacochem properti glycosid pharmaceut formul recommend drug intraven form oral form percentag bioavail oral tablet capsul solut ideal assess compar pharmacokinet data oral administr obtain intraven administr full descript radiochem biochem method studi assai plasma urin concentr drug metabolit accuraci sensiv specif method state calcul area curv auc long distribut phase cardiac glycosid account area calcul extrapol elimin phase infin bioavail order magnitud accept cardiac glycosid individu variat defin small glycosid vitro dissolut rate determin subsequ alter pharmaceut formul process creat submit adequ vitrodissolut rate studi instanc depend thein vitro find extent modif vivocomparison rate extent absorpt formul furnish singl dose multipl dose plasma concentr studi advis submit studi steadi state plasma concentr chronic oral administr multipl dose studi demonstr substanti proport drug excret unmetabol urin urinari assai accept compar bioavail studi quot quot clinic investig factor affect efficaci safeti gener remark clinic efficaci glycosid demonstr patient group suffici size clinic syndrom form princip indic cardiac glycosid left ventricular failur rapid atrial fibril clinic efficaci safeti depend individu patient factor data obtain healthi volunt appli presenc factor influenc factor youth ag disturb renal hepat function assess pharmacokinet studi case factor influenc pharmacodynam hypokalaemia thyroid dysfunct recommend provid full assess clinic relev effect glycosid patient atrial fibril estim plasma concentr difficult highli desir essenti quantit data cardiac function cardiac index patient heart failur regular sinu rhythm cardiac glycosid produc posit inotrop effect prevent occurr tachyarrhythmia plasma concentr data obtain record drug correl plasma level appear undesir effect advers reaction occur studi carefulli monitor advers reaction cardiac glycosid symptom overdosag extracardiac cardiac advers reaction arrhythmia number patient studi necessarili larg investig carefulli design execut record clinic studi prefer patient complic factor mention data obtain patient complic exclud se quot quot difficulti develop adequ dosag recommend recommend dose includ load dose base sound pharmacokinet evid claim dosag regimen varianc normal usag base document observ clinic syndrom rapid atrial fibril abnorm renal hepat thyroid function cardiac surgeri cardiovers specif claim made safeti efficaci clinic condit pharmacokinet pharmacodynam studi carri quot quot recommend respect data sheet direct folder dosag recommend recommend dosag children elderli patient group requir special dosag regimen multitud intrins extrins pharmacokinet pharmacodynam factor affect therapeut efficaci cardiac glycosid occur clinic situat dosag recommend dose dose interv therapeut measur base clinic data condit diminish renal function hepat failur hypo hyperthyroid youth ag proper warn cardiac glycosid condit hypokalaemia hypercalcaemia hypomagnesaemia cardiovers cardiac surgeri interactionsif indic interact occur clinic relev studi detail mention direct folder precautionsal inform therapeut measur accident overdosag deliber poison provid quot quot fix combin view narrow therapeut index cardiac glycosid care indi vidual titrat dosag fix combin cardiac glycosid drug extrem meet standard set norm protocol note guidanc fix combin product annex iv clinic investig oral contracept quot quot gener note guidanc read light norm protocol direct eec direct eec intend sole assist applic interpret document respect specif clinic problem involv establish safeti efficaci oral contracept present note compil primarili contracept mind hormon activ administ oral women evid contracept product subject medicin legisl investig approach requir assess efficaci safeti analog necessarili ident contracept prepar consist compon investig elucid point list note guidanc fix combin product properti individu compon contribut total effect contracept consid modif recogn efficac safe minor chang dosag oestrogen replac accept oestrogen simplifi investig provid theoret basi formul appear sound quot quot clinic pharmacolog studi clinic pharmacolog studi perform oral contracept case fix combin compon meet standard set norm protocol section part chapter iia paragraph design provid data pharmacolog action action man virtu contracept effect attain pharmacolog effect reproduct system process includ hypothalam pituitari activ ovarian endocrin secret ovul endometri histolog biochem activ cervic mucu vagin cytolog secret effect tubal function studi human subject investig anim degre progestogen oestrogen androgen corticosteroid hormon anti hormon activ product compon man appreci quantit studi effect androgen anti androgen clinic pharmacolog phase difficult conclus point drawn anim studi side effect occur efficaci investig natur hormon activ princip metabolit suspect drug interact impair efficaci product advers effect detect product type limit popul includ involv liver function adren activ lipid carbohydr metabol thyroid haemostat mechan quot quot clinic investig efficaci safeti clinic studi oral contracept meet standard set norm protocol part chapter ii principl born mind trial popul popul studi compar countri countri propos introduc product realiz dietari habit endem diseas bodi weight illiteraci substanti affect result obtain contracept method scope trial clinic investig suffici larg render reliabl calcul efficaci term pearl index life tabl method incid advers reaction practic gener prove desir contracept product incorpor progestagen studi cycl treatment modif exist product investig valid conclus drawn limit materi effect product degre precis alter long term substanti part total popul studi contracept period month quarter total data relat prolong larg scale studi oral contracept rule conduct multi centr basi data centr gain substanti experi product includ total analysi studi admiss histori take clinic examin time admiss trial provid detail record risk factor rel contra indic element subsequ relev assess efficaci suppos advers effect ag obes smoke habit alcohol cardiovascular diseas psychic disord symptom migrain endocrin metabol disord epilepsi anaemia disord haemostat system renal disord hepat disord tumour prior obstetr gynaecolog contracept histori recent current drug intak record find point lead exclus subject trial record data recommend contracept studi individu patient data record recogn form advoc world health organ trial subject investig interv month subject take part studi period gynaecolog examin includ cervic smear examin breast weight blood pressur test glycosuria close record menstrual histori suspect advers reaction intercurr ill advers event note patient record chang libido regist subgroup detail laboratori examin perform detect chang normal endometrium hepat function lipid metabol haematolog paramet protein spectrum serum electrolyt urin composit adren activ carbohydr metabol paramet effect anticip view pharmacolog toxicolog find clear abnorm detect patient beexamin clinic find record irrespect subject continu part trial patient admit studi presenc risk factor function disord time admiss undergo regular examin respect trial case contracept failur data pregnanc condit neonat embryo record possibl patient failur assess subject withdraw studi reason withdraw record subject determin time resumpt menstruat fertil effect subsequ pregnanc follow subject shown signific variat metabol function determin return normal termin trial analysi data gener data relat efficaci cycl control advers reaction laboratori find present investig programm individu studi analyz find correl factor capabl affect find ii efficaci pregnanc occur studi detail analysi individu case present iii cycl control data cycl control record present manner incid sever menstrual irregular spot breakthrough bleed amenorrhoea clear variat individu period time discern extent event regard accept trial subject investig iv laboratori find abnorm laboratori find analyz inter alia respect correl clinic find subject concern absolut rel efficaci safeti oral contracept regard effect degre contracept efficaci attain product emploi field condit normal popul attain contracept method obtain wide accept lesser degre efficaci accept outweigh advantag term safeti toler provid chanc contracept failur quantifi explain text made user oral contracept regard harm advers effect sever prolong oral contracept current provid result persist derang menstrual bleed pattern long term persist withdraw post market studi whilst direct eec eec impos requir post market studi conduct applic propos market oral contracept type urg possibl continu long term clinic investig monitor subsequ introduct product concern greatli facilit assess report suppos advers reaction oj annex user inform oral contracept quot quot gener text intend inform oral contracept provid user product packag leaflet articl direct eec note present text direct exclus woman product select written technic languag packag leaflet suppos provid inform physician pharmacist consider extens case advis separ technic inform direct user text drawn light current knowledg relat oral contracept progestogen oestrogen emploi inhibit ovul contracept type adapt text requir text repres gener standard situat consid provid detail extens inform omit point nation situat irrelev text present manner readili understood averag user order inform necessarili follow present note guidanc quot quot natur product natur product purpos intend mean product destin oral contracept gynaecolog treatment made clear quot quot consult doctor section includ statement type consult doctor start prepar determin suitabl consult doctor chang oral contracept condit gener inadvis oral contracept import doctor suffer ill clot leg lung stroke heart attack angina pectori suspect cancer tumour unusu vagina bleed found jaundic reason doctor reason pregnant condit doctor special precaut advis type contracept found suffer time disord breast discharg breast diabet high blood pressur high blood fat level migrain heart diseas kidnei diseas epilepsi deaf mental depress fibroid uteru gall bladder diseas reason doctor smoke habit particulari heavi smoke increas chanc side effect medicin includ pain reliev quot quot product section includ clear instruct dai tablet time dai tablet relev durat ingest cycl order tablet arrang fix order packag dai subsequ cycl treatment start clear advic user act tablet tablet forgotten withdraw bleed occur warn condit reliabl prepar impair vari natur dosag product indlud cycl treatment prepar higher dose previous simultan drug occurr vomit sever diaarhoea quot quot gener inform advic degre reliabl prepar gener term user advis inform doctor surgeon consult reason take oral contracept import diagnosi treatment user recommend consult doctor prescrib product regular interv agre addit sever symptom occur whilst reason pregnant restart treatment interrupt restart treatment pregnanc lactat user inform event stop take product time onset period resumpt fertil advis doctor unusu time woman wish pregnant advis month stop product reproduct function return complet previou pattern quot quot advers reaction commonli occur advers reaction list indic common start treatment effect list includegastrointestin symptom mild headach mammari discomfort swell increas weight chloasma mild depress effect menstrual cycl term product concern common sever advers reaction mention thrombosi cholestasi list provid warn sign justifi consult doctor mammari discharg nodul format sever monthli bleed pattern mark vagin secret vertigo faint jaundic sudden impair vision sudden pain chest abdomen pain swell leg sever headach migrain unexpect symptom annex vi data sheet antimicrobi drug quot quot gener remark wide rang antimicrobi product complex inform requir suitabl product case select optim emploi advantag standard extent present technic inform product type present document intend replac modifi exist futur nation intern guidelin present data sheet fich techniqu packag insert suggest topic attent paid document antimicrobi drug drawn inform word note guidanc antimicrobi drug irrespect mode administr pharmaceut form present inform antimicrobi drug comparison antimicrobi agent mention gener defens constitut essenti element understand proper product view possibl resist micro organ data sheet antimicrobi agent date revis quot quot gener format text section arrang head accord articl direct eec composit microbiolog pharmacokinet indic contra indic pregnanc lactat warn precaut interact dosag instruct advers reaction human toxicolog treatment overdosag storag stabil packag form section document appli strictli type present antimicrobi agent extern oral appli drug poorli absorb suffici mention fact includ detail pharmacokinet absorpt kind drug consider increas circumst damag skin intestin state section relev antimicrobi agent microbiolog classif natur mode action drug group micro organ sensit drug data base test multipl recent isol epidemiolog unrel strain speci effect claim special attent devot micro organ sensit insensit unexpect regard natur drug text extent resist develop rapidli condit occur occurr cross resist antimicrobi agent mention break point mic minimum inhibitori concentr data includ inform order meaning meet standard sensit micro organ list group tabl order increas mic valu specif briefli respect microbiolog method emploi determin mic valu size inoculum origin organ number strain test medium date studi differ mic mbc minimum bacteriocid concentr valu narrow larg state therapeut concentr attain bacteriocid vitro mention provid clinic relev micro organ concern site concentr attain signific degre synerg antagon antimicrobi drug found pharmacokinet advis group inform human pharmacokinet subsect absorpt distribut biotransform excret bioavail absorpt bioavail activ drug factor influenc import extent degre rate absorpt list ii distribut plasma level antimicrobi drug clinic relev inform regard distribut point import averag maximum trough serum plasma concentr administr dose administ dosag regimen time interv maximum concentr attain individu variat drug concentr larg half life plasma penetr bodi fluid relev indic toxic drug penetr intracellularli state distribut predominantli extracellular suffici free drug concentr plasma relev therapeut organ tissu drug penetr poorli ey prostat cn list anim studi drug accumul organ tissu clinic toxicolog relev state iii bio transform pattern bio transform antimicrobi drug import includ data metabolit relev antimicrobi toxic effect iv excret excret pattern drug import metabolit excret urin bile faec percentag total dose administ clinic relev concentr attain list relev indic excret sputum indic made clear drug diseas caus micro organ sensit field desir restrict indic antimicrobi drug order preserv us long period accept give summari organ tissu microbi disord treat effect desir mention specif diseas clinic us drug defin term diseas point drug unsuit treat condit prophylact indic list proper mention diseas concern gener specif term provid drug purpos adequ demonstr gener field indic surgic infect paediatr infect inadmiss situat form administr drug state lactationit state drug excret milk risk sensit infant warningsoth antimicrobi drug cross hypersensit cross resist occur list relev possibl superinfect insensit micro organ mention dosag instruct useth usual dose clinic situat drug differ substanti list specif state adapt dosag renal failur presenc concomit diseas drug young drug children neonat prematur infant dosag schedul children ag provid dose express kilogram dai older children adult total dose relev special dose regimen ag person physiolog declin renal function render maximum safe total dose entir therapi list compat infus drug annex vii clinic test requir drug long term introduct gener requir clinic trial annex direct eec part note guidanc advis clinic trial demand long term plan design pre market longterm studi account specif problem rais type drug diseas gener guidelin exlud specif recommend therapeut class quot quot definit long term cpmp defin long term carcinogen guidelin medicin administ regularli substanti period life continu minimum period month frequent intermitt manner total exposur similar drug therapi classifi occasion infrequ analges occasion toothach headach prescript antibiot repeat anaesthet ga long term ii intermitt antibiot regularli prescrib chronic bronchiti regular analges dysmenorrhoea iii prolong treatment epilepsi hypertens rheumatoid arthriti heart failur iv life long usecategori iii iv consid long term appli drug current medic practic bring drug categori irrespect recommend compani concern ii constitut long term sens present note guidanc depend circumst case natur disord risk thought involv novelti compound exampl illustr meant exclus list quot quot investig efficaci long term studi evid long term efficaci gener assum efficaci short term establish propos properli control studi formul dosag propos evid provid efficaci maintain long term repeat interrupt relev object criteria efficaci subject criteria patient enter trial defin respect diagnosi presenc risk factor repres popul treat drug extrem ag group elderli children appropri includ efficaci gener evid propos present control studi adequ number compar patient scientif valid defin end point criteria efficaci sampl size suffici demonstr adequ signific differ case signific differ control drug demonstr calcul power confid interv sensit trial suffici show relev differ random control trial carri placebo emploi case type studi carefulli design execut contribut supplementari evid efficaci durat studi vari depend purpos trial natur drug suffici account spontan variat diseas effect drug disord complianc occur season variat believ influenc diseas respons therapi account arrang trial interpret result evalu result includ analysi patient alloc treatment control group includ withdraw reason reason patient fail complet studi period record descript fulli document critic event occur withdraw therapi requir efficaci establish short term studi dose level higher propos long term studi evid efficaci base adequ number studi actual dose dose rang propos quot quot investig safeti long term studi drug short term import evid provid adequ number patient monitor rule occurr frequent advers reaction defin frequenc complic claim low frequenc advers reaction support compar studi total clinic experi gener includ data larg repres group patient expos drug month irrespect indic case applic justifi investig larger number patient shorter period time month relev deal drug intermitt drug sole indic rare diseas smaller number patient accept patient fulli monitor clinic biochem haematolog advers reaction drug effect immun system exact requir necessarili vari natur drug disord advers effect relat compound natur fulli monitor group rule compris part total clinic experi relat long term data individu patient receiv drug longer period present specif point attent drug propos long term pre market studi provid complet pictur long term advers reaction manufactur urg undertak adequ post market monitor ii evid need accumul drug propos dosag schedul schedul safe evid supplement clinic evid safeti iii long term increas likelihood concurr drug attent paid problem drug interact iv advers reaction season occurr photosensit evid safeti demonstr advers reaction occur categori patient elderli children receiv drug evid safeti patient establish advers effect occur categori patient propos drug safe categori exclud patient evid safeti base adequ number studi subset drug propos vi investig perform determin withdraw symptom rebound effect occur drug stop effect distinguish mere recrudesc origin symptom vii advers effect occur higher dose propos evid safeti base adequ number studi propos dose rang quot quot fix combin eec note guidanc fix combin product principl present note guidanc appli fix combin compound requir individu case depend natur compound origin fix combin propos annex viii steroid anti inflammatori compound treatment chronic disord introduct note guidanc read light gener requir set norm protocol direct eec quot quot definit document relat applic registr steroid anti inflammatori product intend primarili symptomat long term treatment disord rheumatoid arthriti osteoarthrosi disord joint muscl tendon term anti rheumat anti phlogist commonli languag character drug note primarili intend appli drug produc remiss quot quot stage clinic investig initi short term studi patient dai initi clinic studi undertaken patient serv defin anti inflammatori effect prepar advers reaction occur short term estim approxim dosag rang studi conduct placebo medium term studi patient week subsequ control studi advis compar anti inflammatori properti product dose level studi drug similar type fulli effect dose long term clinic investig note guidanc drug long term fact product intend long period indic mean greatest import point view efficaci safeti studi effect prolong efficaci pattern long term efficaci drug type gener adequ defin control studi month major indic claim drug type primarili rheumatoid arthriti long term studi relat condit season variat rheumatoid arthriti account arrang trial interpret result osteoarthrosi ankylos spondyl claim indic long term investig perform condit extent durat work depend total clinic evid drug avail similar studi rheumatoid arthriti long term clinic investig attent devot factor influenc result form treatment prolong natur phase patient concomit therapi note irrespect type trial analges drug materi anti inflammatori effect supplementari therapi aris treatment report separ ii safeti respect number patient durat treatment note guidanc drug long term exact requir bound vari extent countri climat variat temper climat drug gener year warmer climat treatment suspend summer trial design account season variat advers effect dosag pattern emploi practic trial patient includ substanti number elderli quot quot analges antipyret activ specif analges antipyret activ claim impli investig directli control studi includ short term doubl blind comparison placebo comparison compound quot quot clinic paramet clinic paramet studi give clear pictur extent disord symptom physic function influenc exist set criteria diagnosi grade rheumatoid arthriti regard basi quot quot extrapol result disord joint tendon bursa treat anti inflammatori analges drug differ patholog import studi therapeut effect drug type defin carefulli diagnos clinic condit extrapol result disord permiss patholog clinic close alli juvenil rheumatoid arthriti claim indic drug justifi studi conduct children suffer diseas quot quot side effect care studi advers effect natur frequenc sever claim frequenc advers effect lower product type support adequ evid obtain administr fulli effect dose assess materi attent devot question gastro intestin toler effect blood haemopoiesi effect platelet aggreg advers reaction anticip light anim pharmacolog toxicolog extent major advers reaction dose relat data reason drop out clinic studi throw light sever advers effect pharmacolog toxicolog data suggest drug stimul suppress immun respons interfer significantli immun system work undertaken therapeut dose determin effect clinic import quot quot interact interact drug prescrib concurr case elderli look clinic trial care record concurr medic specif studi interact drug concurr undertaken reason present annex ix anti epilept anticonvuls drug quot quot gener note concern primarili clinic evalu medicin intend long term epilept disord properli design long term clinic studi essenti submit short term studi special aspect efficaci toler safeti experi date show manufactur physician advis irrespect legal oblig continu studi drug type regist market order detect unusu effect long term advers reaction alter therapeut effect long period note guidanc drug long term quot quot investig earliest phase toler studi gener desir clinic assess anti epilept drug perform clinician experienc medic evalu manag epilepsi quot quot select patient earli stage therapeut studi advis select individu suffer type seizur defin frequenc patient select main therapeut studi prefer stabl form epilepsi receiv drug therapeut respons previou therapi studi includ investig therapeut outcom patient degre sever epilepsi recogn interest patient anti epilept drug evalu combin establish drug treatment earlier phase evalu approach gener essenti patient incomplet control exist drug constitut import subgroup studi view defin spectrum activ drug case essenti previou drug prescrib suffici long period attain steadi state blood level previou treatment stabl continu studi compound administ efficaci compound combin determin equal import assess efficaci drug initi therapeut studi perform hospit patient essenti phase studi effect safeti test drug outpati includ engag normal daili activ quot quot pharmacokinet bioavail exist anti epilept drug exampl present kinet problem signific therapeut control linear kinet alter protein bind activ metabolit kinet explor need drug includ inform degre individu variat clinic relev kinet paramet reason data paramet submit adequ number patient investig close relat concern drug interact exist anti epilept drug characterist narrow therapeut margin complex relationship dose serum level rais problem bio avail substanc chemic similar exist drug attent problem note guidanc bioavail quot quot criteria efficaci earli studi continu observ desir stage subsequ reduct frequenc seizur main clinic paramet efficaci assess ambul particularpetit mal case telemetri advis effect eeg behaviour record systemat studi irrespect correl anticonvuls potenti drug subsequ work reduct frequenc sever seizur measur quantifi control condit import assess social work capac time measur benefit decreas advers reaction mind recommend data obtain effect dose level serum level monitor emploi paragraph quot quot compar studi placebo patient convuls avoid placebo comparison assess benefit drug addit inadequ regimen assess effect form epilepsi petit mal drug test againt placebo full placebo comparison feasibl ethic accept convuls epilepsi import phase evalu carri control random clinic trial drug compar drug combin drug emploi seizur question quot quot serum level dose respons evalu effect dose relat side effect consid complet clear impress gain drug therapeut toxic rang includ serum level studi import determin serum concentr monitor therapeut situat meaning advis practic monitor paramet propos salivari level signific reliabl adequ studi quot quot advers reaction event occur treatment carefulli record regard neurolog psycholog involv thought process gait speech coordin nystagmu lethargi problem aris long term clinic observ supplement laboratori test quot quot interact anti epilept pharmacotherapi infrequ perform combin drug signific studi detect clinic import drug interact carri studi includ anti epilept drug combin practic give rise interact exist anti epilept drug phenytoin barbitur carbamazepin interfer metabol type drug involv enzym induct inhibit advis conduct studi detect effect type involv drug dosag critic cardiac glycosid anticoagul oral contracept interact alcohol quot quot durat trial principl set note guidanc drug long term applic anti epilept anticonvuls drug document observ patient treat month order assess safeti efficaci drug long term data relat safeti patient quot quot special claim anti epilept claim special properti psychostimul effect claim substanti control clinic trial special design purpos quot quot fix combin epilept patient treat anticonvuls initi individu adjust dose drug import case individu variat dose respons curv vari kinet narrow therapeut margin special rational fix combin drug convuls disord gener undesir accept extens field experi year mixtur fact toler practic note guidanc fix combin product quot quot children light annex direct eec part chapter iii final paragraph epilept drug accept unrestrict children suffici experi gain group patient type infantil spasm akinet seizur determin dosag serum level effect long term studi design detect effect learn intellig growth puberti point paragraph studi conduct subsequ market annex investig bioavail quot quot gener remark bioavail studi evalu perform vivo dosag form requir gener knowledg pharmacokinet drug broadli type bioavail studi studi develop product comparison exist formul note annex direct eec whilst refer pharmacolog part chapter clinic pharmacolig part chapter ii section pharmacokinet studi set requir respect studi bioavail reflect fact medicin product subject pharmacolog pharmacokinet therapeut studi direct report studi gener includ precis data absorpt fate drug draw clear conclus adequaci reliabl bioavail form market number specif situat aris question bioavail assum especi import studi extens explicitli situat present note note number topic commonli dealt aspect bioavail fact relat pharmacokinet matter refer made separ note guidanc human pharmacokinet studi quot quot definit present purpos bioavail mean rate extent deliveri site action activ drug ingredi therapeut moieti drug administ pharmaceut form bioavail characterist form necessarili run parallel pharmacolog therapeut effect bioavail gener determin extent rate absorpt drug pharmaceut form import determin pass metabol distinguish absolut bioavail pharmaceut form compar intraven administr rel bioavail compar form administ rout intraven tablet capsul concentr site action rare directli measur indirect paramet emploi quot quot paramet question bioavail commonli aris product administ oral rout present note formul product mind case conveni measur bioavail rule concentr time curv blood activ compon activ moieti metabolit reflect concentr attain site action administr rout rais analog problem requir compar approach studi blood concentr feasibl instanc directli relev effect drug case measur concentr urin pharmacolog effect therapeut efficaci sensit reproduc method accept occasion realist felt undesir lai detail rule method studi bioavail gener point made absorpt medicin individu influenc genet environment dietari nutrit factor ag previou exposur drug order elimin minim factor relat formul conduct compar studi defin control condit studi gener perform crossov design requir fewer subject parallel studi approach stabl isotop label unlabel drug permit simultan administr rout simplifi protocol alongsid bioavail studi conduct empti stomach reason perform kinet studi design determin fate drug stomach fill drug emploi practic quot quot applic full clinic document medicin base chemic substanc form administr stanc assum materi direct eec submit point provid inform bioavail final pharmaceut form requir order draw conclus explicit extens investig bioavail need situat exampl give result studi conduct anim man highli variabl possibl exist variat due mark effect pharmaceut process absorpt import ensur exact dosag drug steep dose respons curv narrow margin therapeut toxic dosag hazard patient event inefficaci substanc close relat rais problem bioavail physico chemic pharmacokinet properti drug subsequ chang pharmaceut formul process alter bioavail pharmaceut process emploi unusu constanc bioavail difficult forese case tablet protect coat slow releas form involv activ substanc compris small part total formul product activ compon theoret experiment ground anticip increas decreas bio avail quot quot applic full document applic relat special similar ident composit exist special applic relat modif exist product evid case repeat studi perform origin special essenti question answer older newer formul bioequival appendix differ bioavail induc signific chang efficaci safeti principl applic substanti departur origin formul involv problem list applic full clinic document exist respect medicin clinic statist adequ bioavail studi compris direct comparison formul man requir order draw conclus usefulli complement pharmacokinet studi therapeut trial case minor modif exist product made vitro comparison older newer formul respect dissolut time profil releas activ compon quot quot situat biolog avail studi studi bioavail gener requir drug intend sole intraven drug destin local therapeut necessarili exclud studi passag gener circul drug oral product requir absorb necessarili exclud studi passag gener circul drug differ quantiti activ substanc pharmaceut form proport activ compon excipi made manufactur provid bioavail demonstr product meet requir vitrotest drug reformul remain ident drug color sweeten preserv drug previous prepar manufactur provid bioavail version meet requir appropriatein vitro test appendix fda definit bioequival feder regist vol januari bioequival drug product mean pharmaceut equival pharmaceut altern rate extent absoprt show signific differ administ molar dose therapeut moieti similar experiment condit singl dose multipl dose pharmaceut equival pharmaceut altern equival extent absorpt rate absorpt consid bioequival differ rate absorpt intent reflect label essenti attain effect bodi drug concentr chronic consid medic insignific drug product studi annex xi clinic investig drug treatment chronic peripher arteri diseas quot quot introduct drug influenc peripher haemodynam act vessel wall blood wai commonli market relief intermitt claudic rest pain symptom relat vasospasm drug purpos disput reliabl relev clinic investig perform product question quot quot gener principl clinic section submiss relat drug type meet standard gener consid applic good investig practic indic claim base studi demonstr directli clinic relev statist signific effect patient symptom diseas pharmacodynam find laboratori data result relat specif patholog entiti type patient form administr justif extrapol situat reason patient fail complet studi period record attent devot long term efficaci safeti product effect follow withdraw quot quot specif recommend plan analyz clinic studi intend form part submiss applic urg bear point mind list primarili respect studi intermitt claudic point applic studi peripher ischaem condit definit patientsin order make valid comparison constitut homogen subgroup analysi vital character trial subject time admiss respect number variabl natur site extent peripher vascular disord determin object angiographi perform type patient great respect ii durat sever clinic symptom studi involv lower limb patient displai pronounc reduct abil walk elig trial iii relev dietari habit bodi weight iv intak alcohol smoke habit drug vi presenc relev concurr diseas diabet hypertens vii usual degre physic activ relat iii iv vi vii studi record controlsbecaus symptom due peripher ischaemia fluctuat spontan strongli influenc factor train behaviour measur treat patient compar contemporan control group merit exist drug field wide disput valid refer compound propos comparison present time includ placebo patient selectionalert ambulatori outpati stabl intermitt claudic gener advanc stage chronic arteri diseas select document stabl defin signific chang sever symptom previou month period long observ period character fluctuat symptom patient reach stabil gener measur exercis limit tobacco alcohol diet treatment concomit diseas measur constant trial actual studi begin patient consid stabl condit enter placebo run period intend check stabil assess base line pretreat period standard exercis test carri interv week suffici reproduc result obtain experi shown period week suffici purpos random alloc patient treatment placebo group made run period parametersth essenti paramet reflect measur clinic effect claim effect claim intermitt claudic studi standard exercis toler test treadmil test perform control temperatur condit prolong period acclimat studi supplement score patient assess improv attain whilst drug develop field affect outcom type pure object studi involv venou occlus plethysmographi xenon clearenc measur blood flow muscl doppler blood pressur measur oscillometri calorimetri muscular appear method depend correl extent effect desir clinic method screen product applic wish claim techniqu demonstr clinic us product relev proven compar studi order spontan fluctuat diseas detect develop toler delai advers effect doubl blind phase treatment prolong period month ii enrol patient account season influenc evolut disord occurr advers effect iii relev event occur treatment withdraw trial account analysi resultsani clinic effect obtain extend type patient treat order obtain clear impress care analysi result obtain predefin subgroup requir annex xii pharmacokinet studi man gener present note design provid guidanc assist applic interpret preclin clinic pharmacokinet investig drug irrespect natur mode action rout administr note guidanc read light norm protocol direct eec intend sole assist applic interpret respect specif problem pharmacokinet studi includ drug metabol healthi volunt patient note gener rule point mention necessarili appli substanc studi plan design take account properti indic drug concern relat dose plasma concentr therapeut toxic effect feasibl studi pharmacokinet studi rule order emploi drug condit efficaci safeti essenti establish therapeut schedul evalu relev proce dosag adjust patient appli drug narrow therapeut rang close relat plasma concentr therapeut toxic effect demonstr expect instanc pharmacokinet studi imposs limit provis rais insuper difficulti creat risk test subject case drug partli complet base pharmacodynam clinic studi present note consist section pharmacokinet factor studiedwhich deal absorpt distribut elimin interact advers reaction ii methodolog condit studywhich deal choic administr rout dosag dosag interv choic subject healthi volunt patient wich relev disord patient interf condit choic methodolog sampl analysi data process statist quot quot pharmacokinet factor studi absorpt rate extent activ drug ingredi therapeut moieti absorb data bioavail refer eec note guidanc investig bioavail provid substanc intend produc system effectswhatev rout administr buccal sublingu parenter rectal percutan pulmonari direct indirect data extent absorpt submit comparison intraven dose made prefer precis pharmacokinet analysi entir plasma profil includ absorpt distribut elimin step interrel great extent appli special dosag form delai releas activ substanc prolong durat action claim fail data drug concentr peak cmax time reach peak tmax area concentr time curv auc provid reason suspect physiolog patholog factor presenc food food constitu dairi product stomach function anatom disord gastrointestin tract substanti alter absorpt separ pharmacokinet studi suitabl volunt patient perform substanc intend produc system effectsin case drug high intrins activ topic corticosteroid aerosol respiratori diseas desir studi passag circul pronounc system effect produc principl hold good topic applic drug patient suffer disord skin mucou membran data system effect submit direct pharmacokinet data distribut data adequ mathemat analysi descript interpret analysi model includ data model independ paramet provid percentag characterist bind serum protein studi vivo vitro method case drug activ metabolit high percentag bound plasma protein factor alter protein bind alter therapeut respons studi bind red blood cell blood compon diseas state significantli alter distribut pattern drug decreas volum distribut renal insuffici penetr antibiot cerebrospin fluid mening concentr individu protein drug bound lead alter dosag scheme indic studi suitabl patient relev claim distribut access bodi fluid cerebrospin fluid synovi fluid investig actual drug concentr tissu rare measur data submit desir solv import problem relat efficaci safeti measur feasibl elimin elimin rate parent compound total bodi clearanc elimin half life studi volunt normal elimin mechan patient function disturb elimin mechan natur main rout elimin rel import regard total elimin metabol except drug greater lesser extent subject metabol breakdown human bodi pharmacokinet studi rate biotransform substanti modifi case genet enzymat defici dosag level satur metabol occur induc linear kinet possibl enzymat induct studi metabol clearanc fraction system clearanc high indic pharmacolog activ metabolit qualit activ occasion differ parent drug form ascertain reason suspect contribut signific extent therapeut activ advers reaction man examin suitabl anim model human clinic pharmacolog studi pharmacokinet data metabolit rate format elimin distribut clearanc characterist excret urinari excret defin paramet total cumul amount unchang metabol drug found urin singl dose renal clearanc drug excret half life extent variat individu determin drug show high renal clearanc form pharmacolog activ metabolit signific level predominantli renal clearanc liabl patient renal insuffici elimin accumul characterist patient vari degre reduct glomerular filtrat rate examin quantit data relat elimin rate constant glomerular filtrat rate provid evid present data deriv measur fraction absorb dose excret unchang form urin patient healthi volunt normal renal function renal clearanc constitut substanti proport system clearanc exist tubular secret reabsorpt ph depend secret investig relev claim prolong durat action caus enterohepat recircul rout excret bile milk investig substanc dialys remov haemoperfus interact advers reactionspharmacokinet interact occur absorpt phase distribut elimin phase interact suspect basi anim data expect basi physico chemic pharmacolog properti drug similar compound protein bind enzym induct observ pre clinic studi pharmacokinet due interact measur mechan elucid enzym induct competit renal elimin site type advers reaction due unusu genet pharmacokinet variat rare studi aberr behaviour prospect manner effort put elucid pharmacokinet mechan reason suspect advers reaction caus alter pharmacokinet drug quot quot ii methodolog condit studi scheme administrationboth singl dose multipl dose studi perform recommend dose rang dose interv multipl dose studi continu long establish steadi state concentr drug steadi state level dose depend variabl determin accumul kinet drug predict kinet constant obtain singl dose studi verifi experiment dose includ studi determin dose depend decid linear linear occur dosag level discontinu prolong treatment possibl slow termin decreas plasma concentr reflect exist deep compart investig explain discrep long action substanc appar short elimin half life measur singl dose administr principl detail acknowledg feasibl subject initi studi initi studi gener perform restrict number fast healthi adult volunt defin control condit substanc carri risk healthi volunt cytostat conduct patient suffer diseas drug consid studi patient studi conduct patient suffer diseas drug claim relat dose plasma concentr therapeut effect feasibl studi establish pharmacokinet behaviour drug patient correspond healthi subject full rang kinet studi repeat patient studi pharmacokinet group differ healthi volunt influenc patho physiolog state kinet drug larg number patho physiolog situat clear knowledg requir multipl long expens studi perform licens studi submit market regard properti indic contra indic rout elimin scheme administr drug requir defin dosag calcul pharmacokinet paramet volunt standard condit patient function disturb system absorpt distribut elimin indic render relev kinet studi patient extrem ag infant children elderli drug intend oral administ import studi effect food absorpt factor bodi weight time dai environment factor genet differ alcohol smoke habit concomit medic sex markedli interfer reason markedli influenc result interpret clinic studi kinet studi extend methodolog qualiti pharmacokinet analysi qualiti experiment data serv input analys principl mind sampl number blood sampl larg time adequ determin absorpt distribut elimin phase plasma concentr post absorpt phase determin half live avoid confus distribut elimin half live evid long termin half life plasma concentr longer time urinari data obtain urin collect detect excret parent drug metabolit limit method stabil stabil substanc sampl storag requir care attent analyt procedur specif precis sensit reproduc accuraci recoveri method mention reason safeti technic reason cold analyt method prefer tracer radioact techniqu radioact isotop tracer dose combin quantiti label drug therapeut dose rang case develop suitabl cold analyt method separ assai quantit metabolit parent compound interpret data mathemat method graphic represent comput analysi pharmaco kinet formula state includ confid limit present evalu result summar data obtain subject prefer analyz individu data stage averag pharmacokinet constant obtain proper statist analysi data obtain made inter intra individu variat estim studi number subject larg annex xiii anti angin drug quot quot gener present note design provid guidanc clinic investig determin drug prevent attack angina pectori irrespect natur mode action rout administr drug note guidanc read light norm protocol direct eec intend sole assist applic interpret respect specif problem present anti angin drug clinic profil drug studi acut experiment situat provoc angin attack ischaem episod condit normal practic situat valid data obtain suffici account factor pronounc placebo effect angina pectori substanti variat natur sever symptom subject charact chest pain phase studi possibl sudden withdraw effect drug aggrav symptom consid instanc mechan action appear special effort made investig full studi kinet highli desir distinct drawn angina effort spontan angina angina rest mechan requir separ investig quot quot angina effort angina effort character transient episod chest pain precipit exercis situat result increas myocardi oxygen demand definit select patient patient deem suitabl phase studi coronari insuffici angin pain reproduc ischaem exercis test phase clinic trial field studi patient suffer fromstabl angina effort condit approxim stabl period month clear deterior improv sever condit accur angina effort link fix coronari arteri occlus diseas select coronari arteriographi perform type patient great respect patient rest ecg anomali origin render interpret st difficult exclud trial risk factor smoke hypertens hypercholesterolaemia anti angin drug carefulli record aspect life style relev exercis habit note record class patient exclud studi myocardi infarct preced month month clinic pictur impend infarct suffer angina rest angina due part diseas coronari arteri diseas suffer condit invalid result studi singl blind placebo run period establish verifi stabil patient condit ii assess sever patient condit degre physic effort intens provoc test requir elicit posit respons number angin attack week minimum order includ patient trial iii obtain inform patient capabl diari angina attack nitrat iv accustom patient experiment routin minim subsequ placebo reaction studi elimin carri effect previou treatment run period week week exact durat depend sever frequenc angin attack natur previou treatment period long meet aim acut experiment phase quantifi exercis test run period dai adequ familiar patient exercis test assess physic perform shown period long ensur suffici wash previous administ anti angin drug placebo mark placebo effect treatment angina pectori studi drug field perform placebo refer subject engag studi anti angin drug short act nitrat angin attack occur record compar studi distinguish placebo reaction drug effect initi acut investig plan doubl blind compar trial cross design studi compar agent studi placebo initi clinic studi involv comparison placebo drug recogn studi comparison anti angin drug recogn comparison futur clinic product acut experiment phase angin pain sign acut ischaem state provok control condit reproduc quantifi exercis test requir perform close supervis monitor test perform defin condit time dai period elaps administr drug placebo time respect meal manner administr suggest drug main object variabl maximum work load total work load reach time pain characterist angin natur st dyspnoea maxim heart rate disturb rhythm conduct inappropri blood pressur excess fatigu observ directli concern myocardi ischaem state consid separ observ whilst import regard specif criteria anti angin effect heart rate systol blood pressur record techniqu detect ischaemia studi myocardi oxygen consumpt prove thallium scan isotop angiographi design experi includ studi dose effect relationship durat effect singl dose relationship blood level effect demonstr haemodynam effect automat impli drug effect relief angin pain parallel postul adequ demonstr long term drug clinic studi short term studi last week design control provid data efficaci experiment drug compar agent investig perform doubl blind placebo initi studi provid suffici data dosag durat action advers reaction defin pattern investig medium term studi last month design studi efficaci safeti drug condit close detect decreas increas effect drug prolong studi compar criteria efficaci number angin attack nitrat consumpt exercis toler data nitrat consumpt regard reserv previous constant long period rare case studi exercis toler systemat explor drop rate reason drop side effect myocardi infarct death diagnosi record possibl sudden withdraw drug aggrav symptom consid data evalu result obtain earlier studi regard advers reaction special claim manufactur wish make mechan action interact drug commonli categori patient long term studi note guidanc drug long term clinic observ patient made period year detect period clinic effect defin undesir effect long term studi compar reason drop document clear plan studi angina ecg provok account avoid undu risk patient american heart journal quot quot spontan angina angina rest spontan angina angina rest character chest discomfort ischaem episod occur rest atyp absenc appar elicit factor due coronari arteri spasm vasospast angina patient exhibit mix form angina spasm fix coronari arteri stenosi patient studi separ spasm elicit agent increas coronari arteri tone ergonovin maleat lesser extent alpha adrenerg receptor agonist cold test hazard demand investig consid diagnosi treatment evid procedur accept provid carri coronari care unit standard method limit risk diagnost method angina effort field thallium scan isotop angiographi specif point account circadian fluctuat extrem spontan variabl disord frequent recurr transient ecg typic myocardi ischaemia absenc chest pain difficulti diagnosi frequenc sever complic requir admiss patient coronari care unit ethic consider rais natur diseas method evalu futur gener principl test provid guid compat current practic patient select patient suffer episod uncompl angina rest electrocardiograph ischaemia angiograph evid favour vasospast angina patient suitabl investig techniqu experienc pain painless ischaem episod recur time dai clinic studi subject short act nitrat angin attack occur record short term studi dai perform close supervis special unit efficaci assess criteria occurr spontan evok st detect contin ecg monitor frequenc spontan evok angin attack consumpt short act nitrat doubl blind crossov studi placebo highli desir feasibl consider concern expr sed ab doubl blindrandom control studi placebo patient vasospast angina acut myocardi infarct sudden death report occur patient intract angina ecg evid ischaemia occur trial patient withdrawn trial treatment medium term studi week month compound gener test drug establish main object criteria evalu frequenc chest pain consumpt short act nitrat number episod transient st segment shift detect ambulatori ecg monitor monthli failur treatment lead instabl angina impend myocardi infarct sudden deathsand eventu period respons provoc test side effect carefulli monitor attent devot poss ibl rebound effect withdraw drug long term studi patient suffer vasospast angina treat month year desir case angina effort long term studi perform period year substanc claim effect angina effort angina rest clinic observ patient conduct consist repres group type angina angina rest studi fewer patient accept difficulti studi number patient suffici follow clinic activ defin long term advers effect nomenclatur criteria diagnosi ischaem heart diseas circul annex xiv corticosteroid intend skin quot quot introduct guidelin clinic test hold good principl topic corticosteroid intend skin effect includ local advers reaction principl corticosteroid due common properti anti inflammatori mitosi reduc action inhibit collagen synthesi appar differ stanc fact reflect differ strength concentr rate absorpt elimin note guidanc read light norm protocol direct eec intend sole assist applic interpret respect specif problem present topic form corticosteroid document deal gener characterist topic corticosteroid specif point investig man product corticosteroid activ ingredi document specif appli studi fix combin product gener principl drawn note guidanc fix combin fulli applic advantag combin signific contribut activ ingredi clinic activ demonstr quot quot gener characterist topic corticosteroid penetr local activ local effect corticosteroid penetr skin extent absorpt clinic activ advers reaction demonstr depend substanc corticosteroid factor concentr drughowev concentr vehicl increas concentr result proportion greater effect increas occurr side effect pharmaceut formul penetr activ substanc depend physico chemic properti base presenc compon excipi modifi penetr stratum corneum effect salicyl acid urea propylen glycol antibiot antisept tar site applicationa thick stratum corneum respons weak penetr area sole palm due opposit condit rapid import absorpt occur mucosa scrotal skin eyelid lesser extent skin forehead hair zone head skin conditionpenetr increas damag skin abras patholog situat para keratosi damag stratum corneum recov dai treatment condit applic occlus promot penetr unintention produc napkin babi result applic intertrigin area flexur influenc factor account clinic trial level activ indic activ product control extent cutan penetr intrins activ compound rate elimin corticosteroid customari distinguish depend substanc concentr level activ rang mild moder strong strong strong data tabl annex adapt miller munro drug rough guid direct comparison made prepar borderlin class intermedi class moder strong strong easi defin corticosteroid concentr qualifi inclus categori clinic activ addit influenc vehicl result shift adjac level activ subparagraph view variabl principl desir object comparison exist proprietari product type method valid univers acknowledg view larg number proprietari product methodolog uncertainti feasibl gener accept indic corticosensit dermatosi directli link level activ prepar report tabl ii annex list guidanc adapt nation practic advers effect major corticosteroid normal condit system advers effect due percutan resorpt concern irrevers local side effect skin dermatrophia local advers reaction stronger prepar greater chanc develop advers effect skin atrophi irrevers produc clinic thin skin tele angiectasia purpura striae rosacea perior dermat skin atrophi rebound lead steroid depend impair heal effect ey increas risk glaucoma cataract exacerb mycosi herp simplex miscellan depigment hypertrichosi chanc develop dermal toxic increas durat treatment applic perform occlus site face subparagraph due ingredi base substanc incorpor prepar rare corticosteroid contact allergi occur due suppress immun defenc mask worsen infect observ case erron corticosteroid prepar fungal viral bacteri cutan diseas system effect adult result hypothalamo pituitari adren hpa axi suppress fall plasma cortisol level gener observ dai treatment system effect occur rare occur readili children acut adren insuffici discontinu drug hypercortic arrest growth intracrani hypertens high surfac weight ratio unintent occlus napkin system effect due high penetr strong compound activ metabolit occur factor promot penetr appli risk system effect increas applic larg area larg amount materi prolong administr local system advers effect gener avoid studi defin product strength prepar natur pharmaceut form adequ chosen regard type dermatosi site applic period treatment patient ag product appli condit valid clinic trial quot quot guid clinic test view characterist list paragraph product type examin place corticosteroid question concentr base applic spectrum corticosteroid product determin condit defin pharmacodynam studiesth place product spectrum corticosteroid prepar optim concentr clinic larg extent predict basi result number pharmacolog test anti inflammatori effect mitosi inhibit anim orin vitro corticosteroid induc vasoconstrict man provid preliminari rough guid topic anti inflammatori activ vasoconstrict test deriv mckenzi stoughton archiv dermatolog drug incorpor base compar effect establish corticosteroid prepar approxim equal activ stronger weaker prepar method develop consid desir method investig obligatori regulatori agenc prepar method provid clinic relev method demonstr level activ estim light test confirm clinic investig clinic investig efficaci level activ estim test list confirm clinic product studi random doubl blind investig singl blind investig permit virtual imposs perform doubl blind test parallel group superior instanc conflict opinion express parallel group prefer intra subject half sidestudi left comparison studi type attent paid interact treatment due system transfer side comparison made product activ appli larg area product studi principl base product activ product regard minor modif exist reli comparison product refer adequ vasoconstrict test corticosteroid optim concentr clinic confirm compar investig concentr import possibl increas occurr advers effect concentr subparagraph notabl improv therapeut efficaci report give clear pictur frequenc applic initi period treatment frequenc differ recommend daili desir justifi applic report state site applic area treat amount product week prepar intend occlus influenc effect clinic studi examin valid comparison made treatment condit product test seri condit requir degre inten siti treatment dermatos advis clinic trial list left column tabl iii present group requir prepar strong strong activ moder strong mild product psoriasi atop dermat suitabl condit test efficaci observ clinic form dermatos indic defin place product spectrum corticosteroid prepar definit establish class tabl ii provid requir treatment product class extrapol result skin condit list column tabl iii clinic trial perform skin condit list column extrapol skin diseas indic list suggest provid posit result obtain specif clinic studi conduct adequ methodolog gener principl satisfactori assum substanc activ level dose equal suitabl level sever sever diseas recogn condit normal practic failur treatment product lead stronger prepar dai weaker product mainten treatment mode mention data sheet short term studi week relev investig clinic comparison topic steroid practic appli long period time differ clinic efficaci safeti appar treatment week month reason depend novelti product indic claim studi efficaci safeti long term period month safeti import advers effect inevit run parallel clinic activ possibl occurr studi clinic investig product claim produc frequent sever advers effect establish drug degre activ justifi control studi local advers effect atrophogen activ degre atrophi induc product determin applic product mode includ site applic due thin epidermi alter dermi detect method measur thick skin radio graphic techniqu ultrasonographi histolog measur collagen fibril stereomicroscopi detect topic treatment normal condit week experiment condit applic perform occlus exposur shorter studi toler determin dry skin irrit sensiti zation product base conclus trial patch test perform pharmaceut formul base system action interest practic direct assess effect hpa axi respect plasma cortisol determin give inform studi cortisol metabolit urin perform plasma cortisol determin account diurnal rhythm exhibit plasma cortisol level factor influenc level stress sex season influenc oral contracept heal damag stratum corneum occur dai treatment produc decreas system passag make repeat determin exposur period customari determin plasma cortisol level normal extrem condit applic predispos maximum absorpt desir determin plasma cortisol level condit dai treatment occlus dai occlus normal diseas skin time number patient treat long period abil hpa axi respond stimul usefulli assess determin plasma cortisol stimul adrenocorticotroph hormon compar data refer product condit principl assess fulli extent system absorpt passag circul depend factor precis condit site percentag bodi surfac treat weight product mode subject treat case product manufactur wish claim treatment chronic condit area high absorpt investig absorpt perform applic area product recommend young children system effect record ag group attent ethic aspect investig gt tabl gt gt tabl gt gt tabl gt