Olanzapine

Olanzapine

Olanzapine

From Wikipedia, the free encyclopedia

From Wikipedia, the free encyclopedia

Olanzapine Olanzapine

Systematic

Systematic(IUPA(IUPAC) C) namename

2-Methyl-4-(4-methyl-1-piperazinyl)-10

2-Methyl-4-(4-methyl-1-piperazinyl)-10 H  H _{-thieno[2,3--thieno[2,3-}bb_{][1,5]benzodiazepine][1,5]benzodiazepine}

Clinical data Clinical data

Trade names

Trade names _{Zyprexa (oriinator), many eneri!"Zyprexa (oriinator), many eneri!"}[1][1]

AHFS

AHFS//Drugsc!mDrugsc!m _{MonoraphMonoraph}

"edlinePlus

"edlinePlus _{a#01213a#01213}

#icense data

#icense data

$%

Pregnancy

categ!ry _$+

$%+ (i" not r.led o.t) $!utes !%  administrati!n oral, intram."!.lar  #egal status #egal status $%4 (/re"!ription only) + -only℞  Z /re"!ription Medi!ine $/*M (/re"!ription only) $%℞-only P&armac!'inetic data i!aaila*ility _[2] Pr!tein *inding _3[3]

"eta*!lism _{6epati! (dire!t l.!.ronidation} and +7/12 mediated oxidation) i!l!gical &al%+li%e 33 ho.r", 518 ho.r" (elderly)[3]

,-creti!n _{$rine (59  a" .n!haned dr.), :ae!e" (30)}

[3][4] Identi%iers CAS .um*er _{13253-0#-1} ATC c!de  _{05603 (;6*)} Pu*C&em _{+<' 455} IUPHA$/PS _4 Drugan'  _'=00334 C&emSpider _10442212 U.II  _{$#>4%Z}  ,00 _'00454 C&,I _{+6?=<35}

C&,"# _+6?M=@15

C&emical data

F!rmula ₊

1620 4%

"!lar mass _312843

1D m!del (2m!l) _{<ntera!tiAe imae}

S"I#,S["hoB]

InC&I["hoB]

P&ysical data "elting p!int _{15 C+ (33 C&)}

S!lu*ility in 3ater /ra!ti!ally in"ol.ble in Bater mDm@ (20 C+)

(Bhat i" thi"E) (Aeri:y)

Olanzapine (originally branded Zyprexa) is an atypical antipsychotic. It is approved by the

U.S. Food and Drg !dministration (FD!) for the treatment of schi"ophrenia and bipolar disorder .

#$%

&lan"apine is strctrally similar to clo"apine and 'etiapine. It is a dopamine antagonist and is classified as a thienoben"odia"epine.

&lan"apine as first made in the United ingdom in *+- by li /illy. 0he drg became generic in

-1**. Sales of 2ypre3a in -11 ere 4-.-5 in the US, and 46.75 orldide.#8%

Contents #hide% • *9edical ses o *.* Schi"ophrenia o *.- 5ipolar disorder  o *.: &ther  o *.6 lderly • - !dverse effects o -.* ;arado3ical effects o -.- 9etabolic effects

o -.: ;regnancy and lactation

o -.6 !nimal to3icology

o -.8 &verdose

• :;harmacology

• 69etabolism

• $Society and cltre

o $.* <eglatory stats

o $.- =ontroversy, prosection, lasits and settlements

o $.: 0rade names

o $.6 Dosage forms

• 8<esearch

• 7<eferences

• 3ternal links

Medical uses

#edit%

Schizophrenia#edit%

0he first>line psychiatric treatment for schi"ophrenia is antipsychotic medication hich incldes

olan"apine.#7% _{! =ochrane reviefond, hoever, that the seflness for maintenance therapy is}

difficlt to determine as more than half of people in trials 'it before the si3>eek completion date.#%#needs update%

Comparison

#edit%

?ational Institte for @ealth and =are 3cellence, the 5ritish !ssociation for

;sychopharmacology, and the World Federation of Societies for 5iological ;sychiatry sggest that there is little difference in effectiveness beteen antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on persons preference and

side effect profile.#+%#*1%#**%_{0he U.S. !gency for @ealthcare <esearch and Aality concldes that}

olan"apine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, bt that it is sperior for the treatment of negative and depressive symptoms. When trials enrolling only treatment>resistant patients ere e3clded from

the analysis, olan"apine as sperior for overall assessment.#*-%

 ! -1*: revie of first episode schi"ophrenia conclded that olan"apine is sperior

to haloperidol in providing a loer discontination rate, and in short>term symptom redction, response rate, negative symptoms, depression, cognitive fnction, discontination de to poor efficacy, and long>term relapse, bt not in positive symptoms or on the =linical Blobal

Impressions score. In contrast, pooled second generation antipsychotics shoed speriority to first generation antipsychotics only against the discontination, negative symptoms (ith a mch larger effect seen among indstry> compared to government>sponsored stdies), and cognition scores. &lan"apine cased less e3trapyramidal side effects, less akathisia, bt cased

significantly more eight gain, serm cholesterol increase, and triglyceride increase than

haloperidol.#*:% ! -1*- revie conclded that among *1 atypical antipsychotics, only clo"apine,

olan"apine, and risperidone ere better than first generation antipsychotics.#*6% ! -1** revie

conclded that neither first> nor second generation antipsychotics prodce clinically meaningfl changes in =linical Blobal Impression scores bt fond that olan"apine and amislpride prodce

larger effects on the ;!?SS and 5;<S batteries than $ other second generation antipsychotics

or pooled first generation antipsychotics.#*$%

 ! -1*6 meta analysis of + pblished trials having minimm dration 8 months and median dration $- eeks conclded that olan"apine, 'etiapine, and risperidone had better effects on

cognitive fnction than amislpride and haloperidol.#*8%

&lan"apine is effective in treating the acte e3acerbations of schi"ophrenia.#*7%#*%

Bipolar disorder #edit%

&lan"apine is recommended by the ?ational Institte of @ealth and =are 3cellence as a first line

therapy for the treatment of acte mania in bipolar disorder .#*+% &ther recommended first lines

are haloperidol, 'etiapine and risperidone.#*+% _{It is recommended in combination ith flo3etine as}

a first line therapy for acte bipolar depressionC and as a second line treatment by itself for the

maintenance treatment of bipolar disorder .#*+%

0he ?etork for 9ood and !n3iety 0reatments (=!?9!0) recommends olan"apine as a first line maintenance treatment in bipolar disorder and the combination of olan"apine ith flo3etine as

second line treatment for bipolar depression.#-1%

 ! -1*6 meta analysis conclded that olan"apine pls flo3etine as the most effective among

nine treatments for bipolar depression inclded in the analysis.#-*%

Other #edit%

vidence does not spport the se of atypical antipsychotics inclding olan"apine in eating

disorders.#--%

&lan"apine has not been rigorosly evalated in generali"ed an3iety disorder , panic

disorder , delsional parasitosis or post>tramatic stress disorder . &lan"apine is no less effective

than lithim or valproate, and more effective than placebo in treating bipolar disorder.#-:% It has also

been sed for 0orette syndrome and stttering.#-6%

Elderly#edit%

=iting an increased risk of stroke, in -116 the =ommittee on the Safety of 9edicines (=S9) in the U issed a arning that olan"apine and risperidone, both atypical antipsychotic medications, shold not be given to elderly patients ith dementia. In the U.S., olan"apine comes ith a black bo3 arning for increased risk of death in elderly patients. It is not approved for se in patients

ith dementia>related psychosis.#-$% _{@oever, a 55= investigation in ne -11 fond that this}

advice as being idely ignored by 5ritish doctors.#-8%

 Adverse effects

#edit%

See also: List of adverse effects of olanzapine

0he principal side effect of olan"apine is eight gain, hich may be profond in some cases andEor associated ith derangement in the blood lipid and blood sgar profiles (see

section metabolic effects). ! recent meta>analysis of the efficacy and tolerance of *$

antipsychotic drgs (!;Ds) fond that it had the highest propensity for casing eight gain ot of

the *$ !;D compared ith a S9D of 1.76#-7% _{3trapyramidal side effects, althogh potentially}

serios, are infre'ent to rare from olan"apine#-% _{bt may inclde tremors and mscle rigidity.}

Several patient grops are at a heightened risk of side effects from olan"apine and antipsychotics in general. &lan"apine may prodce non>trivial high blood sgar  in people ith diabetes mellits. /ikeise, the elderly are at a greater risk of falls and accidental inry. Gong males appear to be at heightened risk of dystonic reactions, althogh these are relatively rare ith olan"apine. 9ost antipsychotics, inclding olan"apine, may disrpt the bodyHs natral thermoreglatory systems, ths permitting e3crsions to dangeros levels hen sitations (e3posre to heat, strenos e3ercise) occr .#:%#-+%#:1%#:*%#6%

While olan"apine is sed therapetically to treat serios mental illness, occasionally it can have the opposite effect and provoke serios parado3ical reactions in a small sbgrop of people, ith the drg casing nsal changes in personality, thoghts or behaviorC hallcinations

and e3cessive thoghts abot sicide have also been linked to olan"apine se.#:-%

Metabolic effects#edit%

Direct glcronidation and cytochrome ;6$1 mediated o3idation are the primary metabolic pathays for olan"apine. In vitro stdies sggest that =G;s *!- and -D8, and the flavin> containing monoo3ygenase system are involved in olan"apine o3idation. =G;-D8 mediated o3idation appears to be a minor metabolic pathay in vivo. 0he U.S. Food and Drg

 !dministration re'ires all atypical antipsychotics to inclde a arning abot the risk of

developing hyperglycemia and diabetes, both of hich are factors in the metabolic syndrome. 0hese effects may be related to the drgsH ability to indce eight gain, althogh there are some

reports of metabolic changes in the absence of eight gain,#::%#:6%_{Stdies have indicated that}

olan"apine carries a greater risk of casing and e3acerbating diabetes than another commonly prescribed atypical antipsychotic, <isperidone. &f all the atypical antipsychotics, olan"apine is

one of the most likely to indce eight gain based on varios measres.#:$%#:8%#:7%#:%#:+% _{0he effect is}

dose dependent in hmans#61% _{and animal models of olan"apine>indced metabolic side effects.}

0here are some case reports of olan"apine>indced diabetic ketoacidosis.#6*% _{&lan"apine may}

decrease inslin sensitivity,#6-%#6:%thogh one :>eek stdy seems to refte this.#66% It may also

increase triglyceride levels.#:8%

Despite eight gain, a large mlti>center randomi"ed ?ational Institte of 9ental @ealth stdy fond that olan"apine as better at controlling symptoms becase patients ere more likely to

remain on olan"apine than the other drgs.#6$% &ne small, open>label, non>randomi"ed stdy

sggests that taking olan"apine by orally dissolving tablets may indce less eight gain,#68% _bt

this has not been sbstantiated in a blinded e3perimental setting.

Pregnancy and lactation#edit%

&lan"apine is associated ith the highest placental e3posre of any atypical antipsychotic.

#67% _{Despite this the available evidence sggests it is safe dring pregnancy, althogh the evidence}

is insfficiently strong to say anything ith a high degree of confidence.#67% _{&lan"apine is}

associated ith eight gain hich according to recent stdies may pt olan"apine>treated

patientsH offspring at a heightened risk for neral tbe defects (e.g. spina bifida).#6%

#6+% _{5reastfeeding in omen taking olan"apine is advised against de to the fact that olan"apine is}

secreted in breast milk ith one stdy finding that the e3posre to the infant (in mg per kg of body

eight, that is) is abot *. that to the mother.#:%

Animal toxicology#edit%

&lan"apine has demonstrated carcinogenic effects in mltiple stdies hen e3posed chronically to female mice and rats, bt not male mice and rats. 0he tmors fond ere in either the liver or

mammary glands of the animals.#$1%

Discontination#edit%

0he 5ritish ?ational Formlary recommends a gradal ithdraal hen discontining anti>

psychotic treatment to avoid acte ithdraal syndrome or rapid relapse.#$*% _{De to compensatory}

changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervos system, ithdraal symptoms can occr dring abrpt or over>rapid redction in dosage.

@oever, despite increasing demand for safe and effective antipsychotic ithdraal protocols or dose>redction schedles, no specific gidelines ith proven safety and efficacy are crrently available. Spport grops sch as the Icars ;roect, and other online forms provide resorces and social spport for those attempting to discontine antipsychotics and other psychiatric

medications.#$-% _{Withdraal symptoms reported to occr after discontination of antipsychotics}

inclde nasea, vomiting, lightheadedness, diaphoresis, dyskinesia, orthostatic

hypotension, tachycardia, nervosness, di""iness, headache, e3cessive non>stop crying,

and an3iety.#$:%#$6% _{Some have arged additional somatic and psychiatric symptoms associated ith}

ithdraal in individals treated ith neroleptics.#$$%#$8%#$7%#$% _{0hs, some sggest the ithdraal}

process itself may be schi"o>mimetic, prodcing schi"ophrenia>like symptoms even in previosly

healthy patients.#$+%

O!erdose#edit%

Symptoms of an overdose inclde tachycardia, agitation, dysarthria, decreased consciosness and coma. Death has been reported after an acte overdose of 6$1 mg, bt also srvival after an

acte overdose of -111 mg.#81% _{0here is no knon specific antidote for olan"apine overdose, and}

even physicians are recommended to call a certified poison control center  for information on the

treatment of sch a case.#81% _{&lan"apine is considered moderately to3ic in overdoseC more to3ic}

than 'etiapine, aripipra"ole and the SS<Isand less to3ic than the 9!&Is and 0=!s.#67%

Pharmacology 

#edit%

2ypre3a (olan"apine) *1 mg tablets ( !U)

&lan"apine has a higher affinity for $>@0-! serotonin receptors than D- dopamine receptors, hich

is a common property of all atypical antipsychotics, aside from the ben"amide antipsychotics sch as amislpride. &lan"apine also had the highest affinity of any second>generation

antipsychotic toards the ;>glycoprotein in one in vitro stdy.#8*% ;>glycoprotein transports a

nmber of drgs across a nmber of different biological membranes inclding the blood>brain barrier , hich cold mean that less brain e3posre to olan"apine reslts from this interaction ith

the ;>glycoprotein.#8-%

$ecept! r

 i(n")

[#3] i!l!gic acti!n and n!tes

[#4] 5-6>1 222 ntaoni"t8 5-6>1= 55 E 5-6>1' 10#1 E 5-6>1? 220 E 5-6>2 284

<nAer"e aoni"t8 May .nderlie the Fatypi!alityF o: the neBer antip"y!hoti!" lie olanzapine8 May !ontrib.te to "edatin e::e!t"8

$ecept! r

 i(n")

[#3] i!l!gic acti!n and n!tes

[#4]

5-6>2= 118 <nAer"e aoni"tDantaoni"t8

5-6>2+ 1082 <nAer"e aoni"t8 May .nderlie the appetite-"tim.latin e::e!t" o: olanzapine8

5-6>3 202 ntaoni"t8 /o""ibly re"pon"ible, at lea"t in part, :or it" antiemeti! a!tion8

5-6>5 1212 E

5-6># 80 ntaoni"t8

5-6> 10582 ntaoni"t8

G1 112

ntaoni"t8 @iely re"pon"ible :or the ortho"tati! hypoten"ion "een Bith it" ."e8[#4] G1= 2#3 ntaoni"t8 G2 315 ntaoni"t8 G2= 18 ntaoni"t G2+ 28 ntaoni"t8 M1 2#

ntaoni"t8 @iely the !hie: re!eptor re"pon"ible :or the anti!holineri! e::e!t" "een Bith olanzapineH" ."e8[#4]

M2 #385 ntaoni"t8

M3 528# ntaoni"t8 /o""ible role in type 2 diabete" "ide-e::e!t"8[#5]

$ecept! r

 i(n")

[#3] i!l!gic acti!n and n!tes

[#4]

M5 85 ntaoni"t8

'1 0833 ntaoni"t8

'2 3800

ntaoni"t8 @iely re"pon"ible :or the therape.ti! e::e!t" o: olanzapine aain"t the po"itiAe "ymptom" o: "!hizophrenia8[#4]

'2@on 31 ntaoni"t8

'2%hort 28 ntaoni"t8

'3 4 ntaoni"t8

'4 14833 ntaoni"t8

'5 2 ntaoni"t8

61 281 <nAer"e aoni"t8 @iely re"pon"ible :or the "edatiAe e::e!t" o: olanzapine8[#4]

62 44 ntaoni"t8

64 I10000 ntaoni"t8

&lan"apine is a potent antagonist of the mscarinic 9: receptor ,#88% hich may nderlie its

diabetogenic side effects.#8$%#87% _{!dditionally, olan"apine also e3hibits a relatively lo affinity for}

serotonin $>@0*, B!5! !, beta>adrenergic receptors, and ben"odia"epine binding sites.#-%#8%

0he mode of action of olan"apineHs antipsychotic activity is nknon. It may involve antagonism of dopamine and serotonin receptors. !ntagonism of dopamine receptors is associated

ith e3trapyramidal effects sch as tardive dyskinesia(0D), and ith therapetic effects.

 !ntagonism of mscarinic acetylcholine receptors is associated ith anticholinergic side effects sch as dry moth and constipation, in addition it may sppress or redce the emergence

of e3trapyramidal effects for the dration of treatment, hoever it offers no protection against the development of tardive dyskinesia. In common ith other second generation (atypical)

antipsychotics, olan"apine poses a relatively lo risk of e3trapyramidal side effects inclding 0D,

de to its high affinity for the D* receptor over the D- receptor .#8+%

 !ntagoni"ing @* histamine receptors cases sedation and may case eight gain, althogh

antagonistic actions at serotonin $>@0-= and dopamine D- receptors have also been associated

ith eight gain and appetite stimlation.#71%

Metabolism

#edit%

&lan"apine is metaboli"ed by the cytochrome ;6$1 systemC principally by iso"yme *!- and to a lesser e3tent by -D8. 5y these mechanisms more than 61 of the oral dose, on average, is

removed by the hepatic first>pass effect.#-% _{Drgs or agents that increase the activity of =G;*!-,}

notably tobacco smoke, may significantly increase hepatic first>pass clearance of &lan"apineC conversely, drgs hich inhibit *!- activity (e3amplesJ =iproflo3acin, Flvo3amine) may redce

&lan"apine clearance.#$%

Society and culture

#edit%

"eglatory stats#edit%

&lan"apine is approved in the U.S.!. by the Food and Drg !dministration (FD!) forJ

• 0reatment K in combination ith flo3etine K of depressive episodes associated

ith bipolar disorder  (December -11:).#7*%

• /ong>term treatment of bipolar I disorder  (anary -116).#7-%#7:%

• /ong>term treatment K in combination ith flo3etine K of resistant depression (9arch

-11+).#76%

• &ral formlationJ acte and maintenance treatment of schi"ophrenia in adlts, acte

treatment of manic or mi3ed episodes associated ith bipolar I disorder (monotherapy and in combination ith lithim or sodim valproate)

• Intramsclar formlationJ acte agitation associated ith schi"ophrenia and bipolar I

mania in adlts

• &ral formlation combined ith flo3etineJ treatment of acte depressive episodes

associated ith bipolar I disorder in adlts, or treatment of acte, resistant depression in

adlts#7$%

• 0reatment of the manifestations of psychotic disorders (September *++8#78%K9arch -111).

#77%

• Short>term treatment of acte manic episodes associated ith bipolar I disorder  (9arch

-111).#77%

• Short>term treatment of schi"ophrenia instead of the management of the manifestations

of psychotic disorders (9arch -111).#77%

• 9aintaining treatment response in schi"ophrenic patients ho had been stable for

appro3imately eight eeks and ere then folloed for a period of p to eight months

(?ovember -111).#77%

li /illy has faced many lasits from people ho claimed they developed diabetes or other diseases after taking 2ypre3a. In -118, /illy paid 4711 million to settle ,111 of these lasits.

#7% In -117, li /illy agreed to pay p to 4$11 million to settle *,111 more lasits.#7+%

In -11+, li /illy pleaded gilty to a criminal misdemeanor charge of illegally marketing 2ypre3a

for off>label se and agreed to pay 4*.6 billion.#1%#*%

 ! ?e Gork 0imes article based on leaked company docments conclded that the company had

engaged in a deliberate effort to donplay olan"apineHs side effects.#-% 0he company denied these

allegations and stated that the article had been based on cherry picked docments. 9ost of the docments ere disclosed as the reslt of lasits by individals ho had taken the drg, thogh

other docments had been stolen.#:% li /illy filed a protection order to stop the dissemination of

some of the docments hich the dge believed to be confidential and Lnot generally appropriate

for pblic consmptionL.#:% _{0emporary innctions re'ired those ho had received the docments}

to retrn them and to remove them from ebsites.#6% _{dge ack 5. Weinstein issed a permanent}

 dgement against frther dissemination of the docm ents and re'iring their retrn by a nmber

of parties named by /illy.#:% _{&n anary , -117, dge ack 5. Weinstein refsed the lectronic}

Frontier FondationHs motion to stay his order .#$% _{0he docments given to 0he ?e Gork 0imes}

by im Bottstein sho that senior /illy e3ectives may have kept important information from doctors abot 2ypre3aMs links to obesity and its tendency to raise blood sgar K both knon risk

factors for diabetes. The Times of /ondon also reported that as early as *++, /illy considered

the risk of drg>indced obesity to be a Ltop threatL to 2ypre3a sales.#8% _{&n &ctober +, -111,}

senior /illy research physician <obert 5aker noted that an academic advisory board he belonged to as L'ite impressed by the magnitde of eight gain on olan"apine and implications for

glcose.L#8%

%rade names#edit%

&lan"apine is generic and is available nder many trade names orldide.#*%

Dosage forms#edit%

&lan"apine is marketed in a nmber of contries, ith tablets ranging from -.$ to -1 milligrams. 2ypre3a (and generic olan"apine) is available as an orally>disintegrating LaferL hich rapidly

dissolves in saliva. It is also available in *1 milligram vials for intramsclar inection.#$%

Research

#edit%

&lan"apine has been investigated for se as an antiemetic, particlarly for the control

of chemotherapy>indced nasea and vomiting (=I?N). ! -117 stdy demonstrated its sccessfl potential for this se, achieving a complete response in the acte prevention of nasea and

vomiting in *11 of patients treated ith moderately and highly>emetogenic chemotherapy, hen

sed in combination ith palonosetron and de3amethasone.#7%

&lan"apine has been considered as part of an early psychosis approach for schi"ophrenia. 0he ;revention throgh <isk Identification, 9anagement, and dcation (;<I9) stdy, fnded by the ?ational Institte of 9ental @ealth and li /illy, tested the hypothesis that olan"apine might prevent the onset of psychosis in people at very high risk for schi"ophrenia. 0he stdy e3amined 81 patients ith prodromal schi"ophrenia, ho ere at an estimated risk of :8O$6 of

developing schi"ophrenia ithin a year, and treated half ith olan"apine and half ith placebo.

#% _{In this stdy, patients receiving olan"apine did not have a significantly loer risk of progressing}

to psychosis. &lan"apine as effective for treating the prodromal symptoms, bt as associated