IC.AMS.04.06.02 Scientific expert: Dr Philippe NUSS Saint Antoine Hospital, Paris Solian ® in...

IC.A

MS

.04.

06.0

2Scientific expert: Dr Philippe NUSS

Saint Antoine Hospital, Paris

Solian® in schizophrenia

an overview

IC.A

MS

.04.

06.0

2

The information displayed in this program is provided for medical and scientific purposes only

Sanofi-Aventis does not recommend the use of Solian® in any manner inconsistent with that described in the full prescribing information

available in your country

IC.A

MS

.04.

06.0

2

Content

Schizophrenia: both positive & negative symptoms

Pure dopamine antagonism can assure atypicality

Efficacy studies • global evaluation scales• positive and negative symptoms• depression / anxiety subscales

Respecting• cognition • quality of life / socialisation

Tolerability of antipsychotics• EPS• weight gain and metabolic concerns• sexual / endocrine side-effects

Pharmaco-economics of new generation antipsychotics

Dose titration and switching

Pharmacokinetics and drug-drug interactions

IC.A

MS

.04.

06.0

2

Schizophrenia: course of symptoms

Short term0-2 years

Medium term3-6 years

Long term7-22 years

Positive symptoms

frequent major clinical

issue

less fluctuations

more stabledecreasing

Negative symptoms less frequent

becoming more frequent

more stable

predominantmajor clinical

issue

Concerns acute episodesaffective changes

• anxiety• depression

quality of liferehabilitation

Adapted from McGlashan TH, Fenton WS. Arch Gen Psychiatry 1992

IC.A

MS

.04.

06.0

2

Mode of action

IC.A

MS

.04.

06.0

2

Solian’s D2-D3 selectivity is consistent with atypicality

The dopamine cortico-subcortical imbalance in schizophrenia

Positive symptoms

attributable to

• high dopamine release

• overstimulated D2-receptors

in limbic system

Deficit symptoms

attributable to

• low dopamine release

• understimulated D1-receptors

in frontal cortex

Solian®

blocks D2-receptors does not block D1-receptors

Weinberger DR. Arch Gen Psychiatry 1987 Davis KL, Kahn RS et al. Am J Psychiatry 1991

IC.A

MS

.04.

06.0

2

Solian® a pure D2-D3 antagonist alleviates positive symptoms

Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability

Kapur S. in: “Dopamine in the pathophysiology of schizophrenia.” 2003

In limbic region postsynaptic: predominantly D2-D3 receptors blocked by Solian® -> less positive symptoms

IC.A

MS

.04.

06.0

2

Solian® a pure D2-D3 antagonist alleviates negative symptoms also



In prefrontal region presynaptic: predominantly D2-D3 receptors -> feed-back blocked by Solian®

-> enhanced dopamine release

postsynaptic: predominantly D1 receptors D1 receptors are NOT blocked by Solian®

net result: alleviating hypofrontality and negative symptoms

IC.A

MS

.04.

06.0

2

Solian’s pure D2-D3 antagonismminimizes neuroreceptor mediated side-effects

Antipsychotics receptors binding profile

Adapted from Duncan et al. 1989, Sunhara et al. 1991, Sokoloff et al. 1992, Bymaster et al. 1996, Schotte et al. 1996, Schoemaker et al. 1997 + package inserts

Receptor Subtype Receptor affinity Possible clinical effect

Solian® olanzapine quetiapine risperidone clozapine haloperidol

-adrenergic receptors

1

2

-

-

++

-

+++

+

+++

+++

+++

++

+++

-

Hypotension, tachycardia, vertigo, sexual dysfunction

serotonin 5HT2A

5HT2C

-

-

+++

++

+++

+++

+++

+++

+++

++

++

-

Sedation, weight gain

mAch M1-M2 - ++ - - ++ - Anticholinergic effects, cognitive deficit

histamine H1 - +++ ++ +++ +++ - Sedation, weight gain


IC.A

MS

.04.

06.0

2

Efficacy

IC.A

MS

.04.

06.0

2

Few atypicals with proven superiority over conventionals

Effect size versus conventional antipsychotics

meta-analysis of randomised efficacy trials: 10 atypical versus conventional antipsychotics124 randomised controlled efficacy trials (n = 18 272 schizophrenic patients)

Davis JM et al. Arch Gen Psychiatry 2003

* a 0,25 effect size unit corresponds to 4-6 PANSS points or 3-4 BPRS points change

IC.A

MS

.04.

06.0

2

Efficacy: positive symptoms


meta-analysis of 18 randomised controlled trials, schizophrenic patients

Leucht S et al. Am J Psychiatry 2002

IC.A

MS

.04.

06.0

2

Acute exacerbation: comparable to haloperidol

Efficacy on PANSS positive items

double blind randomised study t = 6 weeks, n = 191 acute exacerbations of schizophrenia DSM III R

Möller HJ, Boyer P, Fleurot et al. Psychopharmacol 1997

-53%NS

IC.A

MS

.04.

06.0

2

Early onset responders* rate

analysis of 2 double blind studies

Burns T, Bale R. J Int Med Res 2001 (Analysis of 2 double blind studies:Puech et al. Acta Psychiatr Scand 1998 and Möller et al. Psychopharmacol 1997)

Solian® 400-800 mg/d(n=219)

p = 0,003

p = 0,004

IC.A

MS

.04.

06.0

2

Acute exacerbation: comparable to risperidone

Efficacy on PANSS positive items

-52%NS

double blind randomised, non-inferiority trial t = 8 weeks, n = 228 acute exacerbations of schizophrenia DSM III R

Peuskens J, Bech P, Möller HJ, Bale R et al. Psychiatry Research 1999

IC.A

MS

.04.

06.0

2

Responders rate compared to risperidone (in %)

responders = improvement ≥ 50% (PANSS, BPRS) or “much” to “very much” improved (GCI)n = 244 patients with chronic schizophrenia and a recent exacerbation

Sechter D et al. Neuropsychopharmacol 2002

65,3%71,9%

76,9%

IC.A

MS

.04.

06.0

2

Acute exacerbation: at least as effective as olanzapine

Efficacy on BPRS subscales

double blind randomised, non-inferiority trial, BPRS: primary endpointt = 6 months, n = 377 acute exacerbations of schizophrenia DSM IV

Mortimer A et al. Int Clin Psychopharmacol 2004

IC.A

MS

.04.

06.0

2

Efficacy: negative symptoms


meta-analysis of 18 randomised controlled trials, schizophrenic patients

Leucht S et al. Am J Psychiatry 2002

IC.A

MS

.04.

06.0

2

Improving the whole range of negative symptoms

SANS subscores

randomised double blind multicenter versus placebo, n = 141 schizophrenicpatients (DSM III R), with predominantly negative symptoms (SANS ≥ 60 and SAPS ≤ 50)

Lôo H, Poirier MF, Théron M, Rein W, Fleurot O. Br J Psychiatry 1997

49,5

43,639,9

29,0

43,0 40,9

IC.A

MS

.04.

06.0

2

Efficacy: negative symptoms versus haloperidol

(mean reduction PANSS negative)

After 6 weeks of treatment1 After 1 year of treatment2

double blind randomised study, t = 6 weeksn = 191 schizophrenic patients DSM III R

1. Möller HJ, Boyer P. Psychopharmacol 1997

randomised, open, follow-up study, t = 12 monthsn = 365 schizophrenic patients DSM III R

2. Colonna L, Saleem P. Psychopharmacol 2000

-37% -7,1

p = 0,038 p < 0,0001

IC.A

MS

.04.

06.0

2

Efficacy: depression/anxiety symptoms

versus haloperidol and risperidone

Reduction BPRS depression/anxiety subscore

pooled results of 3 previously published randomised studies, n = 612 chronic or subchronic schizophrenia(DSM III R and IV), acute exacerbation, (disorganised, paranoid of undifferentiated type), t = 4 - 8 weeksPeuskens J, Möller HJ, Puech A. Eur Neuropsychopharm 2002 Möller H, Boyer P, Fleurot O, Rein W. Psychopharmacol 1997Puech A, Fleurot O, Rein W. Acta Psychiatr Scand 1998 Peuskens J, Bech P, Möller HJ et al. Psychiatry Res 1999

IC.A

MS

.04.

06.0

2

Cognitive improvement in patients with predominantly negative symptoms

Solian® 100 mg/d for 4 weeks, n = 19 (10 disorganised, 9 residual schizophrenia DSM III R),mean age 31,6 years - deficit syndrome (SANS > 65/125; SAPS < 30/125)

Vaiva G, Thomas P, Llorca PM et al. Psych Res Neuroimaging 2002

p = 0,0001 p = 0,002 p = 0,001 p = 0,012

177

105

9

8

IC.A

MS

.04.

06.0

2

Quality of lifeversus haloperidol

Heinrich’s Scale

open randomised studyn = 488 patients with (sub)chronic schizophrenia DSM III R, acute exacerbation

Colonna L, Saleem P et al. Int Clin Psychopharmacol 2000

p = 0,003

p = 0,04

p = 0,012

NS

1,12

4,88

2,77

5,41

IC.A

MS

.04.

06.0

2

Quality of lifeversus risperidone

Social and Occupational Functioning Assessment Scale (SOFAS)

double blind randomised, non-inferiority studyn = 309 patients with chronic schizophrenia DSM IV, recent deterioration at entry


p = 0,033

49%

IC.A

MS

.04.

06.0

2

Tolerability

IC.A

MS

.04.

06.0

2

Low EPS profile (AIMS)

double blind randomised study, n = 310 acute exacerbationsof schizophrenia DSM IV


double blind randomised study, n = 377schizophrenic patients DSM IV


-0,16NS

-0,9NS

IC.A

MS

.04.

06.0

2

Low risk of akathisia on the longer term

Patients (in %) with signs of akathisia (Barnes Akathisia Scale)

open randomised studyn = 488 patients with (sub)chronic schizophrenia DSM III R, acute exacerbation, t = 12 months

Colonna L, Saleem P et al. Int Clin Psychopharmacol 2000

p < 0,0001p = NS

IC.A

MS

.04.

06.0

2

High atypicality: effectiveness with minimal EPS

Solian’s high limbic over striatal receptor affinity

D2-D3 occupancy1

Tool: single photon emission tomography (SPET) after injection of [123I ] epidepridein 8 Solian-treated patients (mean dose = 406 mg/d)1. Bressan RA, Erlandsson K et al. Am J Psychiatry 2003 2. Kapur S, Zipursky R et al. Am J Psychiatry 20003. Kapur S, Seeman P. Am J Psychiatry 2001

threshold forantipsychoticefficacy2,3

threshold forprovoking

EPS2,3

IC.A

MS

.04.

06.0

2

High atypicality: effectiveness with minimal EPS

Solian’s fast off-rate from the D2 receptor

Time needed for 50% release from cloned D2 receptors1


1. Seeman P. Can J Psychiatry 2002. 2. Kapur and Seeman 2001 Kapur S in “Dopamine in the pathophysiology of schizophrenia”. Ed: Kapur S, Lecrubier Y at Martin Dunitz Editions, UK 2003 ISBN 1 84184 366 0

• an effective attenuation of the tonic dopamine transmission -> antipsychotic efficacy

• with less distortion of the bursts of the phasic physiological signalling2 -> minimal EPS

IC.A

MS

.04.

06.0

2

Solian® induces little weight gain

Weight gain at 10 weeks (in kg)

Leucht S, Wagenpfeil S et al. Psychopharmacol 2004, integrating data from Allison DB, Mentore JL, et al. Am J Psychiatry 1999; Rak IW, Jones AM et al. Schizophrenia Res 2000 (for*) and Jody D, Saka AR et al. Int J Neuropsychopharmacol 2003 (for**)

0,80

IC.A

MS

.04.

06.0

2

Less clinically relevant weight gain versus risperidone and olanzapine

Weight gain ≥ 7% from baseline

double blind randomised study, n = 309 chronicschizophrenia DSM IV, t = 6 months


double blind randomised study, n = 377schizophrenic patients DSM IV, t = 6 months


p < 0,0004p < 0,05

18%20,6%

IC.A

MS

.04.

06.0

2

Antipsychotic-induced diabetes mellitus

prospective randomised double blind studyn = 101, initially non-diabetic patients, hospitalised for antipsychotic treatment instauration

1. Consensus statement ADA, APA, AACE, NAASO. Diab Care 2004 2. Koro CE, Fedder DO et al. BMJ 2002 3. Lindenmayer JP, Czobor P et al. Am J Psychiatry 2003 4. Mir S,Taylor D. Int Clin Psychopharmacol 2001

Emergence of new onset diabetes attributable to antipsychotic use- multiple case reports1

- confirmed in a case control study2

Different antipsychotics unequally involved- confirmed in a prospective randomised double blind study3

No published report about a potential relation between Solian® and hyperglycemia or ketoacidosis4

as of May 2003, 650 million treatment days worldwide (IMS figures)

IC.A

MS

.04.

06.0

2

Blood glucose evolution

double blind randomised, non-inferiority trialt = 6 months, n = 377 acute exacerbations of schizophrenia (DSM IV)

Peuskens J et al. Int J Psychopharmacol 2004

107 mg/dl

IC.A

MS

.04.

06.0

2

Endocrine/sexual side effects

Comparison with risperidone1

Prolactin elevation with Solian®2

• not dose dependent• decreases as treatment continues• returns to pretreatment levels within 3 months after treatment stop

pooled data from 11 randomised clinical studiesexposure: 125 days Solian®, 47 days risperidone

1. Coulouvrat C, Dondey-Nouvel L. Int Clin Psychopharmacol 1999 2. Schlösser R, Gründer G et al. Neuropsychobiology 2002

IC.A

MS

.04.

06.0

2

Pharmaco-economics

IC.A

MS

.04.

06.0

2

Low withdrawal rate

premature treatment stop leads to relapsere-hospitalisation after relapse is the most important direct cost factor4

1. Colonna L et al. Int Clin Psychopharmacol 2000 2. Sechter D et al. Neuropsychopharmacol 2002 3. Mortimer A et al. Int Clin Psychopharmacol 2004 4. Smith K et al. Br J Psy 1995

8,9%

8,1%

7,2%

13,8%

10,7%

8,6%

IC.A

MS

.04.

06.0

2

Re-hospitalisations and hospital stays

versus haloperidol

13,2 24,8

Solian®:

Souêtre E et al. Encephale 1992

• on annual basis 11,4 hospitalisation days avoided (p < 0,04)• less concomitant medications (p < 0,001)• less need for second adjuvant antipsychotic (p < 0,001)

IC.A

MS

.04.

06.0

2

Shift to ambulatory careSolian® versus risperidone

double blind randomised study n = 198 (at 6 months), patients with chronic schizophrenia DSM IV and a recent exacerbation

Knapp M, Spiesser L, Jourdan S. Submitted for publication. Data from Sechter et al. Neuropsychopharmacol 2002

Solian® 400-1000 mg/dTotal = 41,9 daysof hospitalisation

24,7 17,2

risperidone 4-10 mg/d Total = 52,7 days of hospitalisation

10,442,3

full time hospitalisation

part time hospitalisation

IC.A

MS

.04.

06.0

2

Posology instructions

IC.A

MS

.04.

06.0

2

Former antipsychotic(conventional or atypical)

Tapering off

Solian®: easy to start…easy to switch to

Start Solian®

Without titration

-> start Solian®

- at the therapeutic dose required- without titration§

-> taper off the old antipsychotic- over a 3-4 week period* (by approximately 30-50% every 3-7 days)1

- without washout period2

- previous concomitant anticholinergics should also be stopped progressively

1. Peuskens J. J Int Clin Psychopharmacol 2000, 15(4):S15-S19 2. Solian® Product Information, June 2001 § in patients with renal impairment dose should be adjusted according to Product Information *Slow tapering off the young, the elderly, recently relapsed, patients on clozapine, those previously treated with doses of low potency neuroleptics, patients difficult to stabilise

Without titration, immediately at therapeutic dose§

IC.A

MS

.04.

06.0

2

Solian®: easy to useClear dosing1

Acute exacerbationsPositive symptoms

StabilisationUsual maintenance dose

Chronic and predominantly negative psychosis

800 mg/day (BID)(to max 1200 mg/d)

400 mg/day (OD)

300 to 50 mg/day (OD)If positive symptoms reappear:

increase dose to previous stabilizing level

1. Lecrubier Y et al. Neuropsychobiology 2001 and Peuskens J et al. Psy Res 1999

For acute psychotic episodes, doses should be adjusted according to individual response.For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms.Maintenance treatment should be established individually with the minimally effective dose.For patients characterized by predominant negative symptoms, oral doses between 300 and 50 mg / day are recommended. Doses should be adjusted individually.

IC.A

MS

.04.

06.0

2

Solian®: clear dosing strategyDose equivalence

usual maintenance dose maximum dose a day

chlorpromazine 75 - 300 mg/d 1 000 mg/d

haloperidol 5 - 10 mg/d 30 mg/d

Solian® 400 - 800 mg/d* 1 200 mg/d

olanzapine 5 - 20 mg/d 20 mg/d

quetiapine 300 - 450 mg/d 750 mg/d

risperidone 4 - 6 mg/d 16 mg/d**

Scottish National Health Service Boards & Therapeutics Committees. The Lothian Joint Formulary 2003. Chapter 4.2: Drugs used in psychoses and related disorders.

* in predominantly negative symptoms: 300 - 50 mg/d** doses > 10 mg/day generally have not been shown to provide additional efficacy

IC.A

MS

.04.

06.0

2

Solian®: acute agitationAssociation with benzodiazepines

Background:- Agitation should be controlled in hours, full antipsychotic efficacy takes weeks or months.- Unnecessary sedation is a barrier for optimal patient function and compliance.1

- Solian® is not a sedative agent

Expert consensus guidelines1:2 distinct needs:

• immediate sedation

• AND long-term antipsychotic effect

2 complementary solutions:

• benzodiazepine

• AND a non-sedating antipsychotic

Conclusion:Sedation should not be achieved by increasing the dose of the antipsychotic, but by initial addition of a sedative agent such as a benzodiazepine.2

1. Allen MH et al. Postgrad Med 2001 2. Bridler R et al. Swiss Med Wkly 2003

IC.A

MS

.04.

06.0

2

BZD association with Solian®

High therapeutic effect Low interaction profile

Effect of single doses Solian® and/or lorazepam on alertness

Solian® did not potentiate or antagonise the effects of lorazepamn = 18 healthy volunteers, highly significant (p < 0,001) decrease for lorazepam at 2, 4 and 8 hours

Perault MC, Bergougnan L et al. Hum Psychopharmacol Clin Exp 1998

IC.A

MS

.04.

06.0

2

Pharmacokinetics Drug/drug interactions

IC.A

MS

.04.

06.0

2

Pharmacokinetics of Solian®

in healthy young volunteers

1. Gillet G et al. Eur Neuropsychopharmacol 2000 2. Perault MC et al. Hum Psychopharmacol Clin Exp 1998 3. Canal M et al. Int J Neuropsychopharmacol 2003

50 %excreted unchanged (after i.v. administration)

64 %total in faeces

Two routes of excretion.The renal clearance may be reduced by age and by renal impairment• creatinin clearance 30-60 ml/min: dose should be reduced to half• creatinin clearance 10-30 ml/min: dose should be reduced to a third• creatinin clearance < 10 ml/min: experience lacking, so particular care is recommended in these patients

35 %total in urine

Excretion

No active metabolites. Only traces from the oxydation of the pyrolidin rings, N-deethylation and hydrogenation

limitedMetabolism

16 %plasma protein bound fraction

A relatively low plasma protein binding fraction-> distribution unlikely to be affected by physiological modificationsor by concomitant administered drugs

5,8 l/kgvolume of distributionDistribution

No effect of food on bioavailability, except if a very high carbohydrate meal

43-48 %absolute bioavailabilityBioavailability

3 hours54 ng/ml

Tmax2 (median) (50-200 mg oral)Cmax2

The two peaks merge to one if administered with food

1 hour38 ng/ml

Tmax1 (median) (50-200 mg oral)Cmax1

Absorption

19 l/hplasma renal clearance

42 l/hplasma systemic clearanceNo modification of pharmacokinetic profilefollowing repeated once daily administration reported

12 hoursplasma elimination t1/2 (after oral administration)

Elimination

No interaction at CYT P4501, no interactions with lorazepam2 or lithium3

IC.A

MS

.04.

06.0

2

Solian® is not metabolized via the CYP450 system

Gillet et al. Neuropsychopharm 10/2000,S331-S332 Package Inserts

IC.A

MS

.04.

06.0

2

Solian® is not metabolized via the CYP450 system (continued)

Gillet et al. Neuropsychopharm 10/2000,S331-S332 Package Inserts

IC.A

MS

.04.

06.0

2

Solian® at a glance

Pure D2-D3 selectivity: a unique mode of action• restoring the dopamine imbalance in schizophrenia• minimising side-effects mediated by other neuroceptors

A high limbic over striatal receptor affinity and a fast off-rate from the D2-receptor • explaining a low EPS level

In general a high effect size on schizophrenia symptoms• one of the few atypicals with proven efficacy over conventionals

In acute situations• fast onset of antipsychotic action involving the whole range of BPRS subscales• as effective as haloperidol or atypical antipsychotics in acute positive symptoms• easy and clear posology instructions• easy manageable combination with benzodiazepines whenever necessary

In predominantly negative symptoms • acting on the whole range of negative symptoms • improving depression/anxiety without affecting cognition

On the longer term • low weight gain - low incidence of metabolic side-effects • low sexual / endocrine side effects in daily practice • respecting quality of life / facilitating socialisation • manageable drug-drug interactions

Value for money• less hospitalisation days / shift towards ambulatory care• good therapy adherence

IC.A

MS

.04.

06.0

2

Solian® a pure D2-D3 antagonist alleviates positive symptoms



In limbic region postsynaptic: predominantly D2-D3 receptors blocked by Solian® -> less positive symptoms

IC.A

MS

.04.

06.0

2

Solian® a pure D2-D3 antagonist alleviates negative symptoms also



In prefrontal region presynaptic: predominantly D2-D3 receptors -> feed-back blocked by Solian®

-> enhanced dopamine release

postsynaptic: predominantly D1 receptors D1 receptors are NOT blocked by Solian®

net result: alleviating hypofrontality and negative symptoms

IC.AMS.04.06.02 Scientific expert: Dr Philippe NUSS Saint Antoine Hospital, Paris Solian ® in...

Documents

Transcript of IC.AMS.04.06.02 Scientific expert: Dr Philippe NUSS Saint Antoine Hospital, Paris Solian ® in...