Making Re-integration the Goal... YPrsxa·"\ 0/anzapine ''' Novel antipsychotic power for routine use ZVPREXA• (olanzapine tablets) THERAPEUTIC CLA S SIFICATION - Antipsycholic Agent P HA R MACOLOGY Pharmacodynamic Properties: ZVPREXA" (oianzapine). a thH!OObenzodiazepine, IS an anb· psychotic agent, dosplaying high receptor affinity binding In vitro at serotonin 5-HT.,.., (Ki = 4 and 11 nM, respectively) , dopamine D, , D 2 , D,. D, (Ki = 11·31 nM), muscarinic M, .. (Ki = 1.9-2.5 nM). adrenergic tt,(Ki = 19 nM), and histamine H, (Ki = 7 nM) receptors. In a behav· 10011 paradigm predicbve of antipsycholic actMty, oianzapine reduced conditioned avoidance response on rats at doses lower than 4 times those requored lo produce catalepsy. In a single dose ( 10 mg) PET study in healthy subjects, oianzapone produced higher 5-HT20 than dopamone D2 receptor occupancy The percent of D2 occtJpancy was less than the threshold value predictive of extrapyramodal events. PhannacoklneUc Properties: ZVPREXA IS well absorbed alter oral adrmniStration. reachong peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Plasma con· centrations of orally administered oianzapine were linear and dose proportional in trials studying doses from 1 to 15 mg. The maxmum plasma concentrations (Cmax) of oianzapine after songle oral doses ol5, 10 and 15 mg averaged 7 , 14, and 21 nglml. respecllvely (20 nglmL = 0 . 064~tM). In young healthy volunteers, after once-a-day repealed dosing, steady-state Cmax was appro.,. mately twoce that achoeved after a single dose (eg. 23 ng/mL versus 12 ng/mL for a tQ.mg dose) In the elderly, the steady state plasma concentration was approximately 3-fold higher than that achoeved after a single dose (e.g. 16 ng/mL versus 5 ng/mL for a 5-mg dose). In both, young and elderly, steady-stale concentrations of oianzapone were obtaoned after seven days of once daily dosing. Over ume and dosage range, pharmacol t 50 ng/mL (approximately 0.5 11M). Olanzapine IS thus not likely to cause clinically important pharmacokinetic drug-drug interactions mediated through the metabolic routes outlined above (see PRECAUTIONS, Drug Interactions). Special PopulaUons: In a single dose study onvolvong 24 healthy subjects the mean elimonabon = . et!'tow~ was prolonged in elderly subfects compared with non-<>lderly subjects. as Men Women <65 years (N=B) 2:65 years (N:16) 29 hours 39 hours 49 hours 55 hours Large scale population pharmacokinetic analyses show that the plasma clearance of oianzapone IS lower on elderly versus young subjects, on females versus males, and in non-smokers versus smokers. However, the overal variabiiHy between individuals is larger than the magnitude o1 mpact of the ondivodual factors of age, gender or smokong. on oianzapine clearance and half .life The pharmacokoneuc characteristics of oianzapone (5 mg single dose) were not sOOslantJalty different in patients with severe renal impaorment and on nonnal subjects. Muftipte-dose studies in pauents wrth renal failure, however, have not been performed. No differences on the single-dose pharmacokinetics of oianzapine were noted in subjects woth cfonocaUy signifocant cirrhosis (who were mcost1y smokers) when compared to healthy subjects (all non-smokers). Multiple-dose studies in patients woth hepatiC ompairment, however, have not been performed. No specofoc pharmacokinetic study was conducted to onvestigate ethnicity effects, but a revoew of the climcal pharmacology studies identifoed no omportant differences on the disposition of olanzapone on Gaucasoan subjects versus subjects of Afncan descent. C LINICAL TRIALS The efficaocy of ZVPAEXA" (olanzapine) in the redUCtion of and maintenance of the reduction of the manofestations of schozophrenia and related psychobc disorders was established in 3, well-rontrolled clinicallrials of psychotic inpatients who, al entry mel the DSM·III·R cmeria for schizophrenoa (most with a course at entry ol "chronic with arute exacerbation") and 1 welk:ontrolled c1onoca1 tna1 of psychotoc inpatients and outpatients who, at entry, mel the DSM-III·R cmeria lor sctuz<>phrenoa. schozophrennorm disorder, or schozoalteci!Ve diso-effect dose with no difference, clinically or statJstically, from placebo on any assessment of psychopathology. (3) A 6-week. dose comparison lrial (N=431) compared 3 fixed dosage ranges of ZVPREXA (5 ± 2.5, 10 ± 2.5 and 15 ± 2.5 mg/day 00), ZVPREXA (1 mg/day OD). and haloperidol (15 ± 5 mglday on a BID schedule). There were no statJstically significant differences between groups on efficaocy measures except for the highest dosage range of ZVPREXA. which was statistocally significantly superior lo ZVPREXA, 1 mg. on the BPRS positive psychoSis cluster, PANSS posrtove subscale, and the CGI·S scale. (4) A 6-week comparator-rontrolled lnal (N=1996, 2:1 randomization, ZVPAEXA : haloperidol) compared 1 dosage range of ZVPREXA (5 to 20 mglday OD) and 1 dosage range of haloperidol (5 lo 20 mg/day OD). The arute mean modal doses (for those patients with al least 3 weeks of treatment) were 13.2 mg/day for ZVPREXA and 11.8 mglday for haloperidol. ZVPAEXA was statistocally signtficantly superior lo haloperidol on the BPRS total, the BPRS negative psychosis cluster. the PANSS negative subscale, and the CGI·S scale. ZVPREXA was also stabstoc:ally sogrnficantly supenor to haloperidol on the Montgomery·Asberg Depression Rating Scale (MAOAS). The validHy of this scale in patients With schizophrenia. hoWeVer, Is not established (5) The effeci!Veness of ZVPREXA on long-term therapy, o.e., >6 weeks, was evaluated in 3 double-blind. controlled, extension maontenance trials (of arutelrials 1, 3, and 4 above). Patients who showed adequate clinical improvement following double-blind arute therapy were allowed to contonue on "' a double-blind, long-term extensoon mamlenance phase on their arute dosage regome. Long-term maintenance of treatment response (as defined by continued reduction n sogns and symptoms sufficient to not requore hospitafozation for psychosis) was compared over tJme (894 ZVPAEXA·treated patients; median length ol treatment was 237 days). The percentage of patients maintaln1ng treatment response over one year was compared. ZVPREXA was statistically sognificantly superior to placebo on the one placebo-controlled lnal and was comparable or sta· bstically sognifocanlly superior to the active comparator in 3 of 3 actiVe comparator-rontrolled trials. While the effocecy of ZVPAEXA at a dose of 5 mg/day was not statistically superior to placebo (see (1)), some individual patients receiving this dose had a good acute response, and were well maintained during a one year extension phase. The above trials (including open-label extension) and an additional lrial in geriatric patients with pnmary degenerative dementia of the Alzhetmer's type constHute the primary database (N:2500 patients treated with ZVPREXA, corresponding to 1122.2 patient-years; N=810 patients treated with haloperidol, corresponding 1o 193.0 patient-years; N:236 patients treated with placebo, corresponding to 27.1 patient-years). INDICATIONS AND CLINIC A L USES ZVPREXA" (oianzapone) is indicated for the arute and maintenance treatment of schizophrenia and related psychotoc disorders. In controlled clinical tnals, ZVPREXA was found to improve both positive and negabve symptoms. ZVPREXA has been shown to be effeci!Ve n mantainong clinical improvement dumg one year of contnuabon therapy in patients who had shown an onitlallreatmenl response. CONTRA IN Dl CATIONS ZVPREXA• (oianzapone) is contraindicated on those patients with a known hypersensotivrty to the drug or the excipoenls of the product WARNINGS Neuroleptic Malignant Syndrome: In prernarl120 lUll, 1.9% (4412280) had elevations to >200 lUll, and 0.2% (512280) had elevaticons to >400 lUlL No patien1s had values on exoess of 700 lUlL None of the ZVPREXA·treated patients who had elevated lrarosam· inase values manifested clinical symptomatology associated with liver impairment The maJOrity of trarosaminase elevations were seen dunng the first six weeks of lrealrnenl. Most elevations were tranSient (66%) while patients continued on ZVPREXA therapy, or falling (11%) at the last available measurement. Of the 134 ZVPREXA·Ireated patients whose enzyme levels increased to >120 lUll, 20 discontinued treatment (6 for hepatic, 14 for other reasons) while their ALT (SGPT) values were stil nsing. In 38 ZVPREXA·Ireated patients woth baseline ALT (SGPT) >90 lUll, none experienced an elevation to >400 lUlL . Precauboros should be exerased when usong ZVPREXA on patients with prlH!Xlsting hepatic disorders. on patients who are betng treated wrth potentJalty hepatotoxic drugs, or treatment· emergent sogns or symptoms of hepabc ompaorment appear. n