Nicotine Formulations as OTC Products

restricts฀access฀to฀NRT฀without฀adequately฀considering฀that฀the฀likely฀consequence฀will฀be฀ the฀continued฀dependence฀on฀the฀use฀of฀nicotine-containing฀tobacco,฀which฀is฀extremely฀ harmful฀and฀universally฀available.฀With฀the฀aim฀of฀achieving฀harm฀reduction฀in฀smoking฀ children,฀ pregnant฀ women฀ and฀ patients฀ with฀ cardiovascular฀ diseases฀ or฀ diseases฀ of฀ the฀ respiratory฀tract฀e.g.฀COPD,฀all฀these฀categories฀of฀people฀should฀be฀permitted฀to฀use฀ NRT฀not฀only฀for฀smoking฀cessation,฀but฀also฀for฀reducing฀the฀daily฀cigarette฀consumption฀ to฀an฀optimum฀of฀10฀cigarettesday.฀A฀critique฀of฀the฀current฀situation฀in฀the฀UK฀was฀ published฀in฀2001฀by฀McNeill฀et฀al.฀ [76] . In฀one฀large฀meta-analysis,฀the฀effects฀of฀prescription฀and฀OTC฀settings฀were฀compared฀ in฀terms฀of฀their฀eficacy฀in฀achieving฀smoking฀cessation.฀The฀studies฀compared฀the฀use฀of฀ patch฀and฀gum฀formulations฀of฀nicotine.฀OTC฀success฀rates฀were฀consistently฀higher฀than฀ prescription฀rates฀at฀6฀weeks฀for฀both฀patch฀OR฀=฀1.45;฀CI:฀1.05–1.98฀and฀gum฀OR฀=฀ 2.92;฀CI:฀1.58–5.40,฀and฀remained฀signiicant฀at฀6฀months฀for฀the฀patch฀OR฀=฀3.63;฀CI:฀ 1.74–7.61฀but฀not฀for฀gum฀OR฀=฀1.37;฀CI:฀0.73–2.58฀ [73] .฀Among฀OTC฀and฀prescription฀ gum฀users,฀16.1฀vs.฀7.7฀were฀abstinent฀at฀6฀weeks฀and฀8.4฀vs.฀7.7฀at฀6฀months,฀respec- tively.฀Among฀OTC฀and฀prescription฀patch฀users,฀abstinence฀rates฀were฀19.0฀vs.฀16.0฀ after฀6฀weeks฀and฀9.2฀vs.฀3.0฀after฀6฀months฀ [77] .฀The฀authors฀claim฀that฀NRT฀use฀within฀ clinical฀studies฀does฀not฀follow฀“real-world”฀prescription฀practices.฀Indeed,฀many฀physi- cians฀prescribe฀NRT฀products฀to฀their฀smoking฀patients฀with฀only฀a฀few฀comments฀con- cerning฀their฀administration฀and฀use.฀In฀this฀way,฀lower฀success฀rates฀will฀be฀achieved฀than฀ if฀physicians฀provide฀comprehensive฀advice฀to฀their฀smoking฀patients฀over฀several฀consul- tations฀cf.฀ Chap.฀15 .฀In฀contrast,฀the฀meta-analysis฀is฀correct฀in฀concluding฀that฀there฀is฀ no฀difference฀in฀eficacy฀between฀OTC฀and฀“real-world”฀prescribing.฀If฀the฀OTC฀method฀ of฀supplying฀NRT฀were฀to฀be฀spread฀across฀larger฀population฀segments,฀this฀would฀dra- matically฀increase฀the฀number฀of฀abstaining฀smokers,฀and฀this฀in฀turn฀would฀have฀a฀sub- stantial฀public฀health฀impact.฀In฀the฀United฀States,฀a฀20฀increase฀in฀quit฀rates฀was฀achieved฀ [78] .฀The฀OTC฀method฀resulted฀in฀fewer฀smoking-attributable฀deaths฀and฀in฀increased฀life฀ expectancy฀ [79,฀80] .฀Worldwide,฀NRT฀must฀become฀more฀accessible฀to฀smokers฀by฀remov- ing฀regulatory฀barriers฀e.g.฀France,฀Australia,฀Brazil,฀and฀early฀results฀suggest฀a฀favour- able฀public฀health฀impact฀ [81] .฀Differences฀between฀European฀countries฀concerning฀the฀ sale฀of฀nicotine฀formulations฀are฀listed฀in฀Table฀ 11.5 .฀While฀most฀nicotine฀formulations฀are฀ OTC฀products,฀bupropion฀is฀available฀only฀on฀prescription. An฀interesting฀question฀is฀whether฀the฀change฀in฀NRT฀sales฀from฀prescription฀to฀OTC฀ status฀ affected฀ smoking฀ cessation.฀ To฀ assess฀ this฀ issue,฀ the฀ 1993–1999฀ Massachusetts฀ Tobacco฀Surveys฀were฀used฀to฀compare฀data฀from฀adult฀current฀smokers฀and฀recent฀quit- ters฀before฀and฀after฀the฀OTC฀switch฀ [83] .฀Interestingly,฀no฀signiicant฀change฀over฀time฀ occurred฀in฀the฀proportion฀of฀smokers฀who฀used฀NRT฀at฀a฀quit฀attempt฀in฀the฀past฀year฀ 20.1฀pre-OTC฀vs.฀21.4฀post-OTC,฀made฀a฀quit฀attempt฀in฀the฀past฀year฀48.1฀vs.฀ 45.2,฀or฀quit฀smoking฀in฀the฀past฀year฀8.1฀vs.฀11.1.฀Fewer฀non-Whites฀used฀NRT฀ after฀the฀switch฀20.7฀pre-OTC฀vs.฀3.2฀post-OTC,฀p฀=฀0.002,฀but฀the฀proportion฀of฀ Whites฀using฀NRT฀did฀not฀change฀signiicantly฀20.6฀vs.฀24.0.฀It฀was฀therefore฀con- cluded฀ that฀ there฀ may฀ be฀ no฀ increase฀ in฀ smokers’฀ rates฀ of฀ using฀ NRT,฀ making฀ a฀ quit฀ attempt,฀or฀stopping฀smoking฀after฀NRT฀became฀available฀for฀OTC฀sale.฀There฀appear฀to฀ be฀other฀barriers฀to฀the฀use฀of฀NRT฀besides฀visiting฀a฀physician,฀especially฀among฀minor- ity฀smokers฀ [83] . 11.1 Nic otine 327 Table 11.5 ฀฀฀Interventions฀to฀support฀smoking฀cessation฀in฀several฀European฀countries฀ [82] +฀yes;฀−฀no;฀d.n.a.฀data฀not฀available;฀B฀bupropion;฀op฀on฀prescription;฀NNS฀nicotine฀nasal฀spray;฀ NI฀nicotine฀inhaler;฀NP฀nicotine฀patch Country Training฀of฀health฀ professionals฀and฀ medical฀students Cessation฀ clinics Helplines Price฀incentive฀or฀ reduced฀cost฀for฀ treatment Pharmacotherapies฀ available฀for฀cessation Pharmacotherapies฀available On฀prescription฀only In฀pharmacies,฀ without฀prescription Austria + + + − + B฀+฀NNS฀op + Belgium d.n.a. d.n.a. d.n.a. d.n.a. + NP฀+฀B฀op − Denmark + + + + + B฀op + Finland d.n.a. + d.n.a. d.n.a. + B฀+฀NNS฀op + France + + + + + − + Germany + d.n.a. + d.n.a. + B฀+฀NNS฀op + Greece + + − − + + + Iceland + + + + + − + Ireland + + + − + B,฀NNS,฀NI฀op + Italy + d.n.a. + d.n.a. + B฀op + Luxembourg d.n.a. d.n.a. d.n.a. d.n.a. d.n.a. d.n.a. d.n.a. Monaco d.n.a. d.n.a. d.n.a. d.n.a. d.n.a. d.n.a. d.n.a. Netherlands + + + + + B฀op + Portugal − + − − + B฀op + Spain + + d.n.a. d.n.a. + B฀op + Sweden + + + − + B฀+฀NNS฀op + U.K. + + + + + B฀op + Hughes฀et฀al.฀determined฀whether฀OTC฀NRT฀is฀pharmacologically฀eficacious,฀whether฀ it฀produces฀abstinence฀rates฀similar฀to฀those฀in฀prescription฀settings,฀and฀to฀estimate฀the฀long฀ term฀that฀is,฀greater฀than฀6฀month฀abstinence฀rate฀with฀OTC฀NRT฀ [84] .฀Using฀a฀meta- analysis฀approach,฀studies฀were฀analysed฀that฀compared฀OTC฀NRT฀vs.OTC฀placebo฀or฀stud- ies฀comparing฀OTC฀NRT฀vs.prescription฀NRT฀that฀reported฀abstinence฀rates฀and฀for฀which฀ a฀full฀study฀report฀was฀available.฀Four฀studies฀were฀randomised฀trials฀of฀nicotine฀vs.placebo฀ patch฀with฀ORs฀of฀2.1–3.2.฀These฀outcomes฀were฀homogenous฀and฀when฀combined฀resulted฀ in฀an฀OR฀favouring฀NRT฀of฀2.5฀95฀CI฀1.8–3.6.฀Among฀the฀two฀randomised฀and฀two฀non- randomised฀trials฀of฀OTC฀NRT฀vs.prescription฀NRT,฀one฀small฀study฀had฀an฀OR฀of฀0.3,฀two฀ others฀had฀ORs฀of฀1.0฀and฀1.4,฀and฀a฀fourth฀study฀had฀an฀OR฀of฀3.6.฀These฀results฀were฀not฀ homogenous;฀however,฀when฀combined฀via฀a฀random฀effects฀model฀the฀estimated฀OR฀was฀ not฀less฀than฀1.0฀–฀that฀is,฀OR฀1.4฀95฀CI฀0.6–3.3.฀The฀long-term฀that฀is,฀greater฀than฀6฀ months฀quit฀rates฀for฀OTC฀NRT฀was฀1฀and฀6฀in฀two฀studies฀and฀8–11฀in฀ive฀other฀stud- ies.฀These฀results฀were฀not฀homogenous;฀however,฀when฀combined฀the฀estimated฀OR฀was฀ 7฀95฀CI฀4–11.฀It฀was฀concluded฀that฀OTC฀NRT฀is฀pharmacologically฀eficacious฀and฀ produces฀modest฀quit฀rates฀similar฀to฀that฀seen฀in฀real-world฀prescription฀practice฀ [84] .

11.2 Bupropion

Bupropion฀or฀amfebutamone,฀a฀drug฀belonging฀to฀the฀aminoketone฀class,฀is฀chemically฀ unrelated฀to฀other฀known฀antidepressants฀ [85] .฀Bupropion฀is฀used฀in฀a฀sustained-release฀ form฀for฀smoking฀cessation.

11.2.1 Pharmacodynamics

The฀mechanisms฀by฀which฀bupropion฀acts฀as฀an฀aid฀in฀smoking฀cessation฀are฀not฀known.฀ Bupropion฀has฀been฀shown฀to฀block฀the฀antinociceptive,฀motor,฀hypothermic฀and฀convul- sive฀effects฀of฀nicotine฀in฀in฀vitro฀tests฀and฀animal฀experiments฀ [86] .฀It฀non-competitively฀ blocks฀ [87] ฀the฀activation฀of฀a 3 b 2 - , ฀a 4 b 2 -฀and฀a 7 -neuronal฀nicotinic฀acetylcholine฀receptors฀ nAChRs฀with฀some฀degree฀of฀selectivity฀ [86] ฀and฀it฀functionally฀inhibits฀nAChR฀sub- types฀of฀human฀muscle฀type฀and฀ganglionic฀receptor฀subtypes฀see฀Fig.฀ 4.1 ฀in฀ Chap.฀4 ฀ [87] .฀Bupropion฀is฀thought฀to฀produce฀its฀therapeutic฀antidepressant฀effects฀by฀inhibiting฀ the฀neuronal฀uptake฀of฀dopamine฀and฀noradrenaline฀and,฀to฀a฀small฀degree,฀of฀serotonin฀ [88] .฀ The฀ metabolites฀ of฀ bupropion฀ hydroxybupropion฀ and฀ threohydrobupropion฀ are฀ active฀in฀vitro฀and฀in฀animal฀models฀of฀depression,฀and฀they฀may฀contribute฀to฀the฀thera- peutic฀effects฀of฀the฀parent฀compound.฀Hydroxybupropion฀probably฀plays฀a฀critical฀role฀in฀ the฀antidepressant฀activity฀of฀bupropion,฀which฀appears฀to฀be฀associated฀predominantly฀ with฀long-term฀noradrenergic฀effects฀ [89] .฀Bupropion฀neither฀inhibits฀MAO฀in฀the฀brain฀ nor฀increases฀the฀release฀of฀biogenic฀amines฀from฀nerve฀endings.฀In฀contrast฀to฀amphet- amine฀or฀dexamphetamine,฀bupropion฀has฀low฀abuse฀potential฀ [90,฀91] .฀A฀few฀cases฀of฀ drug฀dependence฀and฀withdrawal฀symptoms฀associated฀with฀immediate฀release฀bupropion฀ have฀been฀reported.฀Bupropion฀produces฀feelings฀of฀euphoria฀and฀drug฀desirability,฀and฀a฀ mild฀amphetamine-like฀effect฀has฀been฀observed฀400฀mg฀bupropion฀ [92] . Bupropion฀is฀devoid฀of฀cardiovascular฀effects฀such฀as฀impaired฀intracardiac฀conduc- tion,฀reduced฀myocardial฀contractility,฀decreased฀peripheral฀resistance,฀orthostatic฀hypoten- sion฀ in฀ both฀ human฀ and฀ animal฀ studies.฀ However,฀ a฀ signiicant฀ increased฀ risk฀ of฀ treatment-emergent฀hypertension฀has฀been฀reported฀in฀a฀small฀number฀of฀patients.฀The฀ drug฀is฀non-sedating฀and฀antagonises฀the฀effects฀of฀alcohol฀and฀diazepam.฀It฀does฀not฀pro- duce฀weight฀gain.฀Activating฀effects฀may฀occur฀in฀susceptible฀patients฀ [93] .

11.2.2 Pharmacokinetic Properties

Maximum฀plasma฀concentrations฀C max ฀of฀sustained-release฀bupropion฀of฀about฀140฀µgl฀ were฀reached฀approximately฀3฀h฀after฀administration฀150฀mg฀ [94] .฀The฀drug฀is฀exten- sively฀degraded฀to฀three฀metabolites฀hydroxybupropion,฀threohydrobupropion฀and฀eryth- rohydrobupropion฀ [94,฀ 95] .฀ Bupropion฀ is฀ converted฀ in฀ human฀ liver฀ slices฀ in฀ vitro฀ to฀ hydroxybupropion฀by฀the฀cytochrome฀P450฀isoenzymes฀CYP1A2,฀CYP2A6,฀CYP2C9,฀ CYP2E1฀and฀CYP3A4;฀CYP2B6฀is฀the฀major฀isoenzyme฀involved฀ [92,฀96] .฀In฀alcoholic฀ liver฀disease,฀the฀t 0.5 b ฀values฀are฀increased฀approximately฀1.5-fold฀with฀large฀interindivid- ual฀differences฀21.1฀vs.32.2฀h฀ [97] .฀According฀to฀data฀from฀a฀recently฀published฀study฀in฀ 519฀outpatients,฀sustained-release฀bupropion฀exhibits฀a฀statistically฀signiicant฀doseplasma฀ level–response฀relationship฀for฀smoking฀cessation฀ [98] .฀The฀eficacy฀of฀sustained-release฀ bupropion฀in฀facilitating฀smoking฀cessation฀was฀found฀to฀be฀related฀to฀dose฀and฀to฀the฀ mean฀metabolite฀concentration.฀The฀probability฀of฀smoking฀cessation฀increased฀with฀the฀ administered฀dose.฀Furthermore,฀the฀occurrence฀of฀AEs฀such฀as฀insomnia฀and฀dry฀mouth฀ was฀positively฀associated฀with฀the฀mean฀plasma฀concentration฀of฀erythro-amino฀alcohol.฀ The฀highest฀predicted฀probability฀of฀quitting฀was฀observed฀at฀the฀highest฀mean฀plasma฀ concentration฀of฀erythro-amino฀alcohol฀in฀combination฀with฀the฀lowest฀number฀of฀smoked฀ cigarettes฀at฀baseline฀ [98] . Genetic฀polymorphisms฀in฀cytochrome฀P450฀2B6฀CYP2B6฀may฀cause฀variability฀in฀ bupropion฀pharmacokinetics฀since฀hydroxylation฀is฀known฀to฀be฀mediated฀by฀CYP2B6.฀ Therefore,฀bupropion฀pharmacokinetics฀were฀studied฀after฀a฀single฀oral฀dose฀of฀150฀mg฀in฀ 121฀healthy฀male฀volunteers฀ [99] .฀The฀amino฀acid฀polymorphisms฀R22C,฀Q172H,฀S259R,฀ K262R฀and฀R487C฀were฀analysed฀and฀compared฀to฀the฀results฀of฀a฀pharmacokinetic฀analy- sis.฀A฀unimodal฀distribution฀of฀bupropion฀and฀hydroxybupropion฀kinetic฀parameters฀was฀ detected฀with฀a฀mean฀range฀AUC฀of฀3.64฀0.89–8.14฀µmol฀hl฀for฀bupropion฀and฀25.5฀ 6.72–75.3฀ µmol฀ hl฀ for฀ hydroxybupropion.฀ Population฀ kinetic฀ analysis฀ revealed฀ that฀ bupropion฀total฀clearance฀via฀CYP2B6฀alleles฀1,฀2,฀5฀and฀6฀did฀not฀differ,฀but฀clearance฀ via฀allele฀4฀was฀1.66-fold฀higher฀compared฀to฀wild-type฀allele฀1฀p฀=฀0.001.฀Corresponding฀ to฀the฀high฀clearance฀of฀bupropion,฀carriers฀of฀the฀CYP2B6฀genotype฀14฀had฀signii- cantly฀higher฀Cmax฀of฀hydroxybupropion฀compared฀to฀all฀other฀genotypes฀p฀=฀0.03.฀Only฀ a฀minor฀fraction฀of฀the฀variability฀in฀bupropion฀and฀hydroxybupropion฀kinetics฀could฀be฀ explained฀by฀the฀known฀CYP2B6฀amino฀acid฀variants,฀in฀particular฀by฀the฀CYP2B64฀