"A NEVER BEFORE NOVEL THERAPEUTIC

OPTION IN TREATING ANXIETY

DISORDERS-TOFISOPAM"

Overview of anxiety and depression

Pharmacology of Tofisopam
Evidence of tofisopam in anxiety and
depression
Tofisopam: Indian Trial
Summary

The common
psychological
disorders

Depression

Anxiety Disorders

Schizophrenia

Depression
affect nearly 340
million people
worldwide,
India sharing a major
portion

What are the symptoms of depression?

Depressed
mood most of
the day, nearly
every day

Low energy

Loss of interest
Loss
of interest
or pleasure
or pleasure
(anhedonia)
(anhedonia)
Poor
concentration
or memory

Sleep
disturbance

Appetite
disturbance/
weight gain

Psychomotor
agitation or
retardation

Feelings of
guilt or
worthlessness

Suicidal
ideation
At least 5 of the following symptoms are present most of the day, nearly daily for at least 2
weeks during the same period. Either symptom (1) / (2) must be present.

Depression - Current Scenario and the Future

Depression and
affects about 10% of
individuals at some
time during their life.

By 2020, Depression
By 2020,
Depression
= most
common
=
most
common
health problem in the
health
problem
in the
developing
countries
developing countries

25-35% patients fail

to respond. High
suicide rates 15%

Depressi
on

Ranked fourth (WHO)

By 2010, Depression =
second most common
health problem after
heart disease

Anxiety

Anxiety is an altering signal,

it warns of impending danger
and enables a person to take
steps to deal with a threat.

Normal anxiety is usually

accompanied by growth,
change, new experiences
and finding new identity and
meaning in life

Pathological anxiety
is inappropriate in
terms of intensity,
duration and response
to a given stimulus
and lead to social and
occupational
impairment

Anxiety Disorders are

Common
Often have an early onset
teens or early twenties

Show 2:1 female predominance

Have a waxing and waning course over lifetime

Types of anxiety disorders

OCD
Panic

GAD

Disorder

Social
anxiety
disorder

PTSD
Phobi
a

Anxiety Disorders: DSM 5

Separation Anxiety Disorder
Selective Mutism
Specific Phobia
Social Anxiety Disorder (Social Phobia)
Panic Disorder
Panic Attack (Specifier)
Agoraphobia

Anxiety Disorders: DSM 5

Generalized Anxiety Disorder
Substance/Medication-Induced Anxiety Disorder
Anxiety Disorder Due to Another Medical Condition
Other Specified Anxiety Disorder
Unspecified Anxiety Disorder

Should Anxiety disorders be taken seriously?

Associated with substantial levels of distress and suffering

Impairment in various domains of functioning, reduced quality of life, and

high cost to society

Carry a relatively high risk for suicidal behaviour

Increased risk of cardiovascular morbidity and mortality, especially panic disorder

Strong relationship between various primary anxiety disorders and secondary

depression and alcohol and other substance use problems

Starcevic, Australas Psychiatry 2011 19: 12

Anxiety disorder across lifespan

Lenz & Wetherell, Dialogues Clin Neurosci. 2011;13:381-399

Anxiety disorders presentation across lifespan

Lenz & Wetherell, Dialogues Clin Neurosci. 2011;13:381-399

HPA Axis and Anxiety

Lenz & Wetherell, Dialogues Clin Neurosci. 2011;13:381-399

ABC Model of Anxiety

A (Alarm, amygdala)
B (Beliefs, basal ganglia)
C (Coping, cortex)
Bystritsky et al, P T. 2013;38(1):30-57

4. Treatment of Anxiety Disorders

Treatment: Pharmacotherapy
Selective Serotonin Reuptake Inhibitors
SerotoninNorepinephrine Reuptake Inhibitors
Antiseizure Medications
Tricyclic Antidepressants
Additional Medications

Action Profiles of Benzodiazepines

Relief of anxiety

Anticonvulsant
action

Sedation
Induction of sleep

Muscle relaxation

Ansseau, M., Doumont, A., Diricq, S.: Methodology required to show clinical differences
between benzodiazepines. Curr Med Res Opin 8, Suppl. 4, 108-114 (1984).

Limitations of current options

1. Daytime

sedation
2. Cognitive impair
3. Accident/fall
4. Reduce QOL
5. Abuse potential
6. Dependence
7. Withdrawal reaction

SSRI/TCA
1. GI

disturbance
2. Sexual dysfunction
3. Insomnia
4. Discontinuation

SNRI
1. GI

disturbance
2. Sexual dysfunction
3. BP
4. Hepatic injury

Major Concerns or
Limitations of Current Options

BDZ

Benzodiazepine
A benzodiazepine is a psychoactive drug
whose core chemical structure is the fusion
of a benzene ring and a diazepine ring.
The first benzodiazepine, chlordiazepoxide
(Librium), was discovered accidentally by
Leo Sternbach in 1955, and made available in
1960 by HoffmannLa Roche, which has also
marketed diazepam (Valium) since 1963
Benzodiazepines enhance the effect of gammaaminobutyric acid

Issues of safety when considering the use of

Benzodiazepines

Journal of clinical psychiatry 63;9, september 2002

Traditional

BDZs - side effects

Induces sedation & hypnosis which is indistinguishable from a

toxic effect except in degree

Cognitive dysfunction, ranging from short-term memory

impairment and confusion to delirium

Disinhibition and other behavioral aberrations - including extreme

agitation, psychosis, paranoia, and depression, sometimes with
violence toward self or others

Withdrawal, in which the individual experiences a continuum of

symptoms from anxiety and insomnia
*J Clin Psychiatry. 2005;66 Suppl 2:9-13, Psychiatric Bulletin (2002)

Traditional

BDZs - side effects

Individuals who take BDZ to sleep on an airplane may end with a

blank in their memories for the period surrounding the trip.

Students who take benzodiazepines before exams in order to relax

or to get sleep are in danger of losing some of the material they
have been studying. Triazolam produced more sedation and
greater impairment of psychomotor performance at the same dose
in healthy elderly persons than in healthy young persons
(Greenblatt et al., 1991).

*J Clin Psychiatry. 2005;66 Suppl 2:9-13, Psychiatric Bulletin (2002)

Traditional BDZs- State dependency

The possibility of BDZs may not cause true amnesia but induce
state dependency

State dependency is a phenomena by which learnings become

dependent on the pharmacological state in which they are
acquired or consolidated and retrieved only when the person is in
that state

The much publicized example of state dependency is Chaplin's

1931 movie , City lights where a millionaire gets drunk and
establishes friendship with the tramp and recognize her when
under the influence & ignore when sober
*Naturally Occurring Benzodiazepines edited by Ivan Izquierdo, Jorge Medina

Traditional BDZs Rebound & habituation

Rebound, an aspect of withdrawal, in which the individual

develops anxiety, insomnia, or other serious emotional reactions
that are more intense than before drug treatment began.

Habituation and addiction, along a continuum from feeling

dependent on the drug to compulsively organizing one's behavior
in a self-destructive manner around obtaining large amounts of the
agent.

*J Clin Psychiatry. 2005;66 Suppl 2:9-13,

Overview of anxiety and depression

Pharmacology of Tofisopam
Evidence of tofisopam in anxiety and
depression
Tofisopam: BE and CT
Summary

Tofisopam - Non traditional BDZ

1. First approved over 35 years ago and currently marketed
in more than 15 countries, has a benign safety profile
and a broad spectrum of clinical activity
2. Tofisopam (marketed under brand names Seriel and
Grandaxin) is a drug which is a benzodiazepine
derivative.
3. tofisopam, a racemic 2,3-benzodiazepine comprised of
R- and S-enantiomers, is unlike traditional 1,4benzodiazepines
4. Like other benzodiazepines, it possesses anxiolytic
properties but unlike other benzodiazepines it does not
have anticonvulsant*, sedative, skeletal muscle relaxant,
motor skill-impairing or amnestic properties with minimal
abuse liability and minimal cognitive impairment.

*While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant
action of classical 1,4-benzodiazepines such as diazepam

Tofisopam Non traditional BDZ

Tablet

Dosage
Form

Each Uncoated
Tablet Contains:
Tofisopam JP
50 mg or 100
mg

indicated for the

treatment of
anxiety and
depression.

Composition

Indications

Tofisopam approved since 1974

Hungary
France
Czech Republic
Russia
Japan
Thailand:
Indonesia
Honk Kong
China
Malaysia
Philippines
Singapore
Vietnam

Pharmacological of Actions

Because of
the

Physical or
psychic

nonsedativ
e property,

dependenc
e have not

it is an ideal
daytime
anxiolytic
agent.

been
observed
even in longterm therapy.

It has no

In
therapeutic
dose range,
tofisopam
does not
potentiate
the effect of
alcohol. The
incidence of
side effects
is relatively
low.

cardio
depressive
effect.

Atypical amongst Benzodiazepines & SSRIs

Pharmacokinetics

When tofisopam was administered orally in healthy adult males, the

blood concentration reached to the maximum after 1 hour of
administration, gradually decreased thereafter and almost
disappeared from the blood after 12 hours.

After oral administration, the metabolic products were mainly detected

in urine

In the in vitro metabolism test using liver microsome, this drug was
mainly metabolized by CYP3A4, or the obstruction of metabolism by
CYP3A4 was indicated.
S Ronai et al, Human pharmacokinetic data on Grandaxin

Dosage and Administration

Dosage should be individualized. Dosage is adjusted depending upon

age and symptoms. The usually recommended daily dose of tofisopam
is 50 mg to 100 mg administered 1-3 times daily. The maximum daily
dose is 300 mg.

Elderly: administered with caution

Pediatric use: Safety in pediatrics has not been established.

Hepatic impairment: should be administered with caution

Renal impairment: should be administered with caution

Side effects
Side effects were observed in 232 cases (2.6%) out of total 8,803 cases

1.1% (CNS)

like drowsiness, staggering

etc.

1.1% (GI)

like dry mouth, nausea and

vomiting, loss of appetite,
constipation, abdominal pain etc.

0.3%

washed-out feeling, feeling of

exhaustion etc.

<0.1%

headache, insomnia, uneasiness, impatience,

depression, numbness of hands and feet,
diarrhea, fever, facial edema, palpitation, high
blood pressure, burning, pain in breast, lactic
secretion, rise in AST and ALT levels, etc.

Rarely

menstrual disorder and

dependency.

Contraindications

Pregnan
cy

Psychosis
and
psychopath
y
accompanie
d by
marked
psychomoto
r agitation,
aggressiven
ess or a
deep
depression

Respirato
ry
insufficien
cy in the
stage of
decompe
nsation

Hypersensi
tivity to
benzodiaze
pines

Warnings and Precautions

1.
2.
3.
4.
5.
6.
7.

severe sleep disturbances

narrow angle glaucoma
myasthenia gravis
organic disorder of the brain
moderate to severe respiratory failure
activities like driving, operation of risky machinery, etc
not to exceed the dosage

Overview of anxiety and depression

Pharmacology of Tofisopam
Evidence of tofisopam in anxiety and
depression
Tofisopam: BE and CT
Summary

Tofisopam in the treatment of anxiety neurosis*

*a relatively mild form of mental illness characterized by extreme
distress and agitation, often occurring without any obvious cause

This is a four week

placebo-controlled,
double-blind,
comparative clinical
trial
compare the efficacy
and adverse effects
of tofisopam with
placebo in the
treatment of anxiety
neurosis.

Sladk R, Dostlov J, Haskovcov V, et al. Act Nerv Super (Praha) 1978 Dec; 20(4) :245-6.

Change in fear item score on HAM-A and improvement on

BATE discrepancy score with tofisopam

Sladk R, Dostlov J, Haskovcov V, et al. Act Nerv Super (Praha) 1978 Dec; 20(4) :245-6.

Tofisopam in anxiety neurosis

50 patients of anxiety neurosis

1 week wash-out period

Tofisopam 150-300mg/day
(n= 25)
4 weeks

Placebo
(n= 25)
x 4 weeks

Follow up at the end of 1, 2 and 4 weeks.

Efficacy measure

Hamilton anxiety scale (HAMA)

BATE inventory
N 5 inventoryClinical global impression (CGI)

V Filip et al, AgressoIogie, 1981, 22: 27-30

Tofisopam in anxiety neurosis

Hamilton anxiety score: Changes seen in male subgroup
Placebo
Tofisopam
HAMA Factor I
(Somatic anxiety

HAMA Factor II
Psychic anxiety

HAMA
Total score

XX, -- p <0.05 and 0.01 (change from baseline)

- p< 0.05 (between groups)

V Filip et al, AgressoIogie, 1981, 22: 27-3

Tofisopam in anxiety neurosis

Hamilton anxiety score: Changes seen in female subgroup
Placebo
Tofisopam
HAMA Factor I
(Somatic anxiety

HAMA Factor II
Psychic anxiety

HAMA
Total score

XX, -- p <0.05 and 0.01 (change from baseline)

V Filip et al, AgressoIogie, 1981, 22: 27-30

Tofisopam in anxiety neurosis

BATE- Discrepancy score (suggests the degree to which pts
anxiety exceeds the usual personality based anxiety levels)

Males

X, -- p <0.05 (change from baseline)

+, ++ -- p< 0.05 and 0.01 (between groups)

Females

Placebo
Tofisopam

V Filip et al, AgressoIogie, 1981, 22: 27-30

Tofisopam in anxiety neurosis: Safety

N 5 inventory

Incidence of drowsiness , fatigue, performance, memory

impairment no significant difference between two Rx groups.
No in daytime vigilance and intellectual function
Improves insomnia

Other adverse events

Mild adverse events (restlessness, jerks in calves) reported in

2 patients subsided on discontinuation.

V Filip et al, AgressoIogie, 1981, 22: 27-30

Tofisopam in anxiety neurosis:

Conclusion

Efficacy

Significant improvement in

HAMA from baseline

HAMA fear score suggesting
antiphobic properties
BATE discrepancy score

Insomnia

Safety

Well tolerated
No serious side effects

Conclusion
The results of this study indicate that tofisopam is an effective
Anxiolytic agent superior to placebo and with minimal side effects

V Filip et al, AgressoIogie, 1981, 22: 27-30

Tofisopam for anxious depressive

syndrome

30 pts with anxious depressive syndrome of unpsychotic origin

Dose range 100-300 mg/day; mean dose 158.3 mg
Duration of treatment 21 days
Efficacy measures: clinical evaluation and Becks scale

Molcan et al, AgressoIogie,

1981, 22: 23-24

Tofisopam for anxious depressive

syndrome

ResultsBecks

Scale

Molcan et al, AgressoIogie,

1981, 22: 23-24

Tofisopam for anxious depressive

syndrome

Results
Clinical

global evaluation

Molcan et al, AgressoIogie,

1981, 22: 23-24

Safety & Conclusion

Tofisopam : significant anxiolytic effect with moderate

psychoenergetic effects
No impairment of attention
No somnolence
Well tolerated with no adverse effects
No change in Lab parameters

Tofisopam is safe and effective for the management of

anxious depression

Molcan et al, AgressoIogie,

1981, 22: 23-24

Tofisopam: Outpatient treatment

Open label, prospective study
325 pts with anxiety associated with various
psychiatric disorders
On treatment for variable period of time
Tofisopam dose 150-300 mg/day
Efficacy measures: self rating scale of Derogatis,
physicians Szobors symptom rating scale.

Varady et al, Ther. Hungarica,1975;

23:153-158

Anxiety states associated with various psychiatric

disorders
Very good to significant improvement

Varady et al, Ther. Hungarica,1975;

23:153-158

Anxiety states associated with various psychiatric disorders

Very good to significant improvement

Varady et al, Ther. Hungarica,1975;

Anxiety states associated with various psychiatric

disorders
Results
Overall

improvement: Total percentage

Varady et al, Ther. Hungarica,1975;

23:153-158

Anxiety states associated with various psychiatric

disorders
Effect as early as 1 week, maximum response by week 3
Effective psychorelaxant in geriatric patients
Increased sociability: better anxiolytic and psychic vigour
Pts with compulsive neurosis: neuroleptic treatment failure-showed best
results
No drowsiness, tiredness
No major effect on concentration and driving skill
Conclusion: Tofisopam may be considered as
psychovegetative stabilizer or harmonizing tranquilizer
agent which may be used without hazard because of the
lack of unwanted and toxic effects.
Varady et al, Ther. Hungarica,1975;
23:153-158

Comparison with Nitrazepam as preanaesthetic medication

Significant reduction in excitement and apprehension

double-blind, randomized study,

47 patients received tofisopam 100mg night before and 100mg on the morning of operation;
49 patients received nitrazepam 5mg and
50 patients received placebo
Br J Anaesth 1980;52(10): 1009-12.

Comparison with Nitrazepam as preanaesthetic medication

Better than Nitrazepam in controlling daytime sedation

Br J Anaesth 1980;52(10): 1009-12.

Better alternative to lorazepam in Anxiety Disorders

Tofisopam
produced
comparative
effectiveness as
that of lorazepam
on HAMA scale
two HAMA factors
(psychic and
somatic) and
clinical global
impression (CGI).

Korean Soc Bio Psychiatry 1997; 4(2):265-71.

Better alternative to lorazepam in Anxiety Disorders

Korean Soc Bio Psychiatry 1997; 4(2):265-71.

No of patients

In mixed anxiety depression with somatic complaints

Am J Psychiatry 1979; 136(2):196-9.

% of patients

In mixed anxiety depression with somatic complaints

Percentage of
patients with
no illness or
mild illness at
week 1 and at
endpoint with
tofisopam and
placebo
group.

Am J Psychiatry 1979; 136(2):196-9.

Better improvement in anxiety and depressive symptoms

Zh Nevrol Psikhiatr IM SS Korsakova 2009; 109(9 supp):44-8.

Improves vegetative dysfunction and sleep quality

Zh Nevrol Psikhiatr IM SS Korsakova 2009; 109(9 supp):44-8.

Tofisopam: Effect on psychomotor skill

and memory
Comparison with
diazepam and
interaction
with
Subjects trained in co-ordination test, choice reaction
test, Flicker
alcohol
fusion test, maddox wing, attention test, time anticipation
test,

Study Design

Double-blind, Cross over design

memory and learning tasks.

Then each subject participated in six sessions of two successive
mornings with 1 wk drug free period between sessions.

Seppl et al, Pshycopharmacology, 1980:

69: 209-218

Better choice in alcohol withdrawal syndrome and predelirium states

Comparison with
diazepam and
interaction with
alcohol

Seppl et al, Pshycopharmacology, 1980:

69: 209-218

Tofisopam: Effect on psychomotor skill

and memory

Results of mistakes in counting suggesting effects on short term m

Number

* - p < 0.05,
*** - p< 001
against placebo.
No significant
change with
tofisopam

Seppl et al, Pshycopharmacology, 1980:

69: 209-218

Tofisopam: Effect on psychomotor skill

and memory

Results
Subjective

feeling of performance at different times

Seppl et al, Pshycopharmacology, 1980:

69: 209-218

Conclusion
Effect as early as 1 week, maximum response by
week 3
Impairment of memory function not seen with
tofisopam moreover failed to enhance the ethanol
induced impairment
No impaired hand eye co-ordination
Well tolerated and safe drug
Conclusion
Psychomotor side effects are significantly less than
diazepam
These
grounds, one may conclude that tofisopam is
a good alternative for diazepam, provided that the doses
used are equipotent as to their anxiolytic effect.
Seppl et al, Pshycopharmacology, 1980: 69:
209-218

No major impairment of driving skill and alertness

Counting down (secs)
(Incorrect answers)
Morning

Evening

Bourdons Test
(secs)
Morning

No of
Errors

Evening

Evening

Difference in value for

Tofisopam and Placebo

-2.5
*

-5

-8.5
**

-10
-15
-20

-14
*

-25
-30
-35
-40

* P <0.01 ** P<0.001; n=61;

-40
**
Dose 50 mg BID

-34
**
Ther Hung 1975;23(4):143-6.

IBS
A good set of bowels is
worth more to a man than
any quantity of brains
Josh Billings (Henry Wheeler
Shaw) 1818-1885
72

Rome III Criteria for IBS

Diagnostic criterion*
Recurrent abdominal pain or discomfort** at least days/month in the last
months associated with two or more of the following:
. Improvement with defecation
. Onset associated with a change in frequency of stool
. Onset associated with a change in form (appearance) of stool
* Criterion fulfilled for the last months with symptom onset
at least months prior to diagnosis
** Discomfort means an uncomfortable sensation not described as pain.
In pathophysiology research and clinical trials, a pain/discomfort frequency of at
least
days a week during screening evaluation is recommended for subject eligibility.

Symptom-based medical
treatment of IBS
Abdominal pain / discomfort

Antispasmodics
Antidepressants
TCAs / SSRIs/
dextofisopam
Alosetron
Tegaserod

Constipation

Diarrhoea

Abdominal
pain /
discomfort

Bloating /
distention

Loperamide
Other opioids
Alosetron

Altered bowel
function

Fiber
MOM/PEG solution
Tegaserod
Brandt, AJG 2002;97:S7
Drossman, Gastroenterology 2002;123;2108

Reduction in bowel movements/day

Month 1

Month 2

Month 3

Follow Up

dextofisopam
200 mg b.d.
demonstrated
efficacy in this
double- blind,
placebocontrolled
study in
patients with
IBS.

Aliment Pharmacol Ther 2008;27:197-206.

In functional disorders of GI tract

Tofisopam
improved anxiety
symptoms in
patients with
functional
disorders of GI
tract

Ter Arkh 2000; 72(10 supp) 23-7.

Role of tofisopam in vertigo, dizziness and/or tinnitus

The medication was found

to be effective in 63.2% of
the patients with vertigo
and/or dizziness, and in
66.7% of the patients with
tinnitus.

100
90
80
70

63.2

66.7

60
50
40
30
20
10
Vertigo &/or Dizziness
Tinnitus
Series 1

Practica Oto-Rhino-Laryngologica 1991; 84(1):113-120

Treatment of psychic disorder accompanying myasthenia gravis

47 patients were treated with

tofisopam two groups (39
patients in myasthenia gravis
and 8 patients in myopathy
group).
Tofisopam was given in dose of
150 300mg/day for 21 days on
average
Overall, 89.36 % of patients
showed very good and
moderately good.

45

44.6

44.6

40
35
30
25
Series 1

20
15
10
5
0
Very good response

Ther Hung 1975;23(4):154-63.

Tofisopam and psychomotor performance

In a double-blind study, 121

patients undergoing oral
surgical interventions were
enrolled and given
tofisopam, diazepam or
placebo.

tofisopam resulted into

minimal changes on the
psychomotor performance
measured 60 minutes after
giving the drug and 30
minutes after the operative
procedure.
Ther Hung 1983; 31(1):19-23.

Effect of tofisopam in treatment of somatoform disorders

Before treatment

After treatment

Depression

17.5 6.1

10.6 4.1*

Reactive anxiety

48 13.1

42 14.4*

Quality of life

18.6 5.5

13.4 2.9*

VAS subjective
evaluation of health
condition

5.5 1.3

3 0.9*

Difference between before and after treatment

* p<0.01

Overview of anxiety and depression

Pharmacology of Tofisopam
Evidence of tofisopam in anxiety and
depression
Tofisopam: Indian Study
Summary

CSR No.SUN/TOFI/1208

Study Treatment
Name

Tofisopam

Lorazepam

Strength

50 mg

1 mg

Dosing Schedule:
Recommended dosage of Tofisopam was 50mg TDS for 4
weeks.
Recommended dosage for Lorazepam was 1mg TDS for 4
weeks

CSR No.SUN/TOFI/1208

Primary Efficacy Parameters

Average change in total score of anxiety
rating scale (HAM-A)
Paramete Tofisopam treatment group Lorazepam treatment group
rs
(n = 122)
(n = 121)
Day 0
Mean
total
score of
HAM-A

Day 28

Reducti
on

30.47 12.02
5.36
4.06

esults expressed as mean SD, * P < 0.05

18.49*

Day 0

Day 28

29.90 16.39
5.17
5.88

Reducti
on
13.55

CSR No.SUN/TOFI/1208

Secondary Efficacy Parameters

Average change in Total score of Item 1 (anxious mood) of
HAM-A scale from baseline

Reduction in total score

Worse

Better

- 1.46
- 2.05

Tofisopam
Lorazepam

CSR No.SUN/TOFI/1208

Secondary Efficacy Parameters

Average change in Total score of Item 2 (Tension) of HAM-A
scale from baseline

Reduction in total score

Worse

Better

- 1.31
Tofisopam
- 1.9

Lorazepam

CSR No.SUN/TOFI/1208

Safety and Tolerability

Type of adverse
events

Tofisopam
treatment group
(n=124)

Lorazepam
treatment group
(n=124)

Constipation

Diarrhea

Dizziness

Dryness of mouth

Forgetfulness

Giddiness

Headache

Itching

Increased irritability

Increased sleep
2
Well tolerated with few side effects, minimal sedation
Drowsiness
4
13

CSR No.SUN/TOFI/1208

Safety and Tolerability

Type of adverse
events

Tofisopam
treatment group
(n=124)

Lorazepam
treatment group
(n=124)

Insomnia

Decreased appetite

Decreased concentration

Nausea

Nervousness

Restlessness

Sedation (day time)

4
7

Tremors

Vomiting

Weakness

No serious adverse events

CSR No.SUN/TOFI/1208

Safety and Tolerability

No significant changes observed in blood pressure and pulse
rate.

Variables

Blood
Systolic
pressur
e
Diastolic
(mmHg)
Pulse Rate
(beats/min.)

Tofisopam Treatment
group
(n=120)

Lorazepam Treatment
group (n=112)

Day 0

Day 28

Day 0

Day 28

127.63
10.33
80.15
7.03
81.74
6.45

123.98
9.13
78.62
6.28
79.28
6.81

127.32
11.49
79.77
7.61
82.55
7.04

123.12
9.80
78.29
6.89
80.30
6.36

Results expressed as mean SD

Dosage
Equivalent chart

CSR No.SUN/TOFI/1208

Conclusion
Tofisopam is safe and effective in the management of Generalized anxiety
disorder (GAD)

Superior anti-anxiety effect than lorazepam shown by

significant reduction in HAM-A total score.
Reduction in
HAM-A scale Item 1 (Anxious mood)
HAM-A scale Item 2 (Tension)

Significant improvement in CGI-S and CGI-I Scores

Well tolerated with few adverse events
No serious adverse events
No significant changes in BP, HR and laboratory findings
from baseline to end of study

Overview of anxiety and depression

Pharmacology of Tofisopam
Evidence of tofisopam in anxiety and
depression
Tofisopam: Indian CT
Summary

Summary

Tofisopam

broad
spectrum of
clinical
activity
marketed in
European &
benign
Asian countries,
Phase II trial aresafety profile
carried out for
IBS in USA

Summary

2, 3 BDZ that structurally differs from 1, 4-BDZs Clear cut

anxiolytic action without sedation for outpatients & working class

Equiefficacious to classical BDZs like Diazepam, Oxazepam, Nitrazepam

& Lorazepam to treat different anxiety states

Significant reduction in somatic & psychic anxiety in both males & females
Increases the ability of patients to cope with daily tasks

In Anxiety- Depressive syndrome

2 times reduction in Becks scores to achieve euthymia
50% patients gets fully remitted after 21 days

Summary

Wider use in psycho-vegetative disorders of neurotic origin

Greater reduction in reactive & personal anxiety within week 2.
Exerts regulatory, harmonizing effect on vegetative & somatic symptoms
Striking results in compulsive neuroses

In Functional disorders of GI tract

Corrects the anxiety syndrome & vegetative dysfunction. Reduces the
transit speed along the intestine in patients with irritated bowels

Summary

Dual action to relieve both depression & anxiety. Can be well

combined with TCAs or SSRIs if required.
Clean Pharmacokinetics Rapid absorption, short half-life
without any accumulated toxic side effects
Better choice in alcohol withdrawal syndrome & predelirium state
Effective tranquilizer of the same potency as diazepam
Both somatic & psychic symptoms improved by day 2
Useful in alcoholic patients who are already retarded, inactive
& depressed. No deterioration of orientation & selfsufficiency
Does not significantly potentiate the effect of alcohol

Summary

Daytime tranquilizer Well tolerated than classical BDZs

No major incidence of AEs

Drowsiness & Fatigue
Dizziness or Walking disturbances
Physical or Psychic dependence over long-term

Improves productivity & mental performance

No cardiotoxicity & lacks muscle relaxant activity
- Safely co-rxed with CVS drugs & neuromuscular diseases
Mood enhancer & psychic energizer

More than 80 clinical trials & marketed in major European & Asian
countries
BID dosing with the last dose preferably before 5 pm

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