Asenapine & agomelatine Pharmacology

1. Asenapine & Agomelatine
1
Dr. Jervin Mano, MD

2. Asenapine
2

3. Introduction
 Schizophrenia : mental disorder characterized by
problems with thought processes and by
poor emotional responses
– Positive symptoms : hallucination
– Negative symptoms : lack of
motivation
– Cognitive disturbances : memory
disorders
 Bipolar disorder: mood disorder with episodes of
an elevated or agitated mood known as mania
alternating with episodes of depression
3

4. Leading Causes of Years of Life
Lived with Disability
1 Unipolar depressive disorders 16,40%
2 Alcohol disorders 5,50%
3 Schizophrenia 4,90%
4 Iron-deficiency anemia 4,90%
5 Bipolar affective disorder 4,70%
6 Hearing loss, adult onset 3,80%
7 HIV/AIDS 2,80%
8 Chronic obstructive pulmonary disease 2,40%
9 Osteoarthritis 2,30%
4

5. Past historic of anti-psychotics : 5

6. Limitations with Current
Treatment
 Effective only in a subset of patients
 Prediction of individual treatment response not possible
 Are associated with safety and tolerability issues
 Extrapyramidal symptoms and akathisia (Haloperidol)
 Prolactin increases (Risperidone)
 Metabolic changes (Olanzapine)
 Weight gain (Olanzapine/Risperidone)
 Cardiovascular risk factors (QTc prolongation) (Quetiapine)
 Clinical practice: a high rate of switching due to limited efficacy and/
or tolerability
6

7. ASENAPINE
 Important new treatment option for patients
with schizophrenia and bipolar disorder
 Psychotropic agent belonging to class of dibenzo-
oxepino pyrroles
 Approved by FDA in Aug 2009
7

8. MOA
 The mechanism of action is unclear
Acts on receptors:
 Serotonin :5-HT1A , 5-HT1B , 5-HT2A , 5-HT2B, 5-HT2C , 5-
HT5A , 5-HT6 , and 5-HT7
 Adrenergic: α1, α2A , α2B, and α2C
 Dopamine :D1 , D2 , D3 and D4
 Histamine :H1 and H2
 No appreciable affinity for muscarinic cholinergic receptors
8

9. Pharmacokinetics
Absorption
 Bioavailability: SL, 35%; swallowed, ≤2%
 Peak plasma time: 0.5-1.5 hr
 Peak plasma concentration: 4 ng/mL
Distribution
 Protein bound: 95%
 Vd: 20-25 L/kg
9

10. Pharmacokinetics
Metabolism
 Metabolized by UGT1A4 and CYP450
(predominantly isoenzyme 1A2)
 Enzymes inhibited: CYP2D6 (weakly)
Elimination
 Half-life: 24 hr
 Clearance: 52 L/hr
 Excretion: Urine (50%), faeces (40%)
10

11. TRADE NAME & COST
US/EUROPE
 Saphris, Sycrest
INDIA
 Asenapt marketed by Sun pharmaceuticals
 5mg 10 tabs - ₹55
11

12. DOSAGE FORMS
 5mg sublingual tablets
 10 mg sublingual tablets
12

13. INDICATIONS & DOSAGES 13

14. Patient Counselling Information
1.Gently remove tablet
Do not crush tablet.
2.Place tablet under tongue and allow it to dissolve completely.
Do not chew or swallow tablet.
Do not eat or drink for 10 minutes.
14

15. WARNINGS
Mortality
 Drug comes with boxed warning of increased mortality in
elderly patients with dementia-related psychosis
 C/I in patients with dementia-related psychosis
Hypersensitivity
 Sep 2011, FDA issues warning of serious hypersensitivity
reactions following drug administerations
 To be administered with caution
15

16. ADVERSE DRUG REACTIONS
Neuroleptic Malignant Syndrome
 hyperpyrexia, muscle rigidity, altered mental status, and evidence
of autonomic instability
1) immediate discontinuation of antipsychotic drugs and other drugs
not essential to concurrent therapy
2) intensive symptomatic treatment and medical monitoring
3) treatment of any concomitant serious medical problems
Hypersensitivity Reactions
 anaphylaxis, angioedema, hypotension, tachycardia, swollen
tongue, dyspnea, wheezing and rash
16

17. ADVERSE DRUG REACTIONS
Oral hypoesthesia
 Reverses in half to one hour after taking the drug
Tardive Dyskinesia
 irreversible, involuntary, dyskinetic movements
Weight Gain
 regular monitoring of weight
Orthostatic Hypotension
 Due to the α1-adrenergic antagonist activity
Application site reactions including oral ulcers, blisters,
peeling/sloughing and inflammation
17

18. ADVERSE DRUG REACTIONS
Leukopenia, Neutropenia, and Agranulocytosis
QT Prolongation
 should be avoided in combination with other drugs known to
prolong QTc
Hyperprolactinemia
 D 2 receptor antagonist
Seizures
Somnolence
Dysphagia
18

19. ADVERSE DRUG REACTIONS
Hyperglycemia and Diabetes Mellitus
 Risk of hyperglycemia-related adverse events
 Patients with an established diagnosis of diabetes mellitus
who are started on atypical antipsychotics should be
monitored regularly for worsening of glucose control
Extra pyramidal syndrome
 Lesser incidence than other antipsychotic drugs
19

20. Extrapyramidal Reactions 20
0
5
10
15
20
25
30
Placebo
Asenapine
olanzapine
Risperidone
Haloperidol
Placebo
Asenapine
olanzapine
Risperidone
Haloperidol
Placebo
Asenapine
olanzapine
Risperidone
Haloperidol
Dyskinesia Akathisia Parkinsonism
Patient Percentage (%)

21. Asenapine And Weight Gain
Short-term trial
21
0
0,5
1
1,5
2
2,5
3
Placebo AllAsenapine(5-
10mg BID)
Olanzapine(5-20mg
QD)
Risperidone(3mg
BID)
MeanChangefromBaselineBody Weight (Kg)
Placebo
AllAsenapine (5-10mg BID)
Olanzapine (5-20mg QD)
Risperidone(3mg BID)
Baseline (kg):
P=81.7
A=78.5
R=86.8
O=78.4
21

22. Drug Interactions
 Asenapine weakly inhibits CYP2D6.
 Should be coadministered cautiously with drugs
that are both substrates and inhibitors for
CYP2D6
22

23. SPECIAL POPULATIONS
 Pregnancy: Risk of foetal toxicity category C
 Lactation : Excretion in is unknown
 Paediatric : Safety and effectiveness have not been
established
 Caution advised in geriatric age group
 Renal Impairment: No dose adjustment needed
 Hepatic Impairment:
 Mild to moderate impairment (Child-Pugh class A or B): Dose
adjustment not necessary
 Severe impairment (Child-Pugh class C): Not recommended

24. OVERDOSAGE
 Reported adverse reactions at the highest dosage included
agitation and confusion.
 No specific antidote available
Management
 ECG taken to evaluate arrhythmias
 Haemodynamic compromise: intravenous fluids and/or
sympathomimetic agents
 In case of severe extrapyramidal symptoms, anticholinergic
medication should be administered.

25. CLINICAL TRIALS
SCHIZOPHRENIA
 Adult patients who met DSM-IV criteria for schizophrenia were
included
 Primary efficacy rating scale was the Positive and Negative
Syndrome Scale (PANSS).
 Trial One
This study enrolled 174 subjects and compared Asenapine (5 mg
twice daily) to placebo, Asenapine was statistically superior to
placebo on the PANSS total score.
Trial Two
This trial enrolled 448 subjects and compared two fixed doses of
Asenapine (5mg and 10mg twice daily) to placebo. Asenapine 5
mg twice daily was statistically superior to placebo on the PANSS
total score.
 Trial Three
Asenapine could not be distinguished from placebo

26. BIPOLAR DISORDER
 3-week, randomized, double-blind, placebo-controlled, and
active-controlled (olanzapine) trial
 Adult patients who met DSM-IV criteria for Bipolar Disorder
were included
 Asenapine was statistically superior to placebo on the
YMRS total score and the CGI-BP Severity of Illness score

27. ADVANTAGES DISADVANTAGES
Sublingual form convinient to
take
Mechanism of action is
unclear
Rapid onset of action Serious ADR of mortality in
geraiatric patients with
dementia related psychosis
Promising safety and efficacy Limited clinical information
available

28. REFERENCES
 Potkin SG, Cohen M, Panagides J Efficacy and tolerability of
asenapine in acute schizophrenia: a placebo- and
risperidone-controlled trial. The Journal of Clinical
Psychiatry 2007 Oct;68(10):1492-500
 Marston HM, Young JW, Martin FD, Serpa KA, Moore CL,
Wong EH, Gold L, Meltzer LT, Azar MR, Geyer MA, Shahid
M Asenapine effects in animal models of psychosis and
cognitive function. Psychopharmacology 2009 May 22

29. Agomelatine

30. Depression
 Mood disorders is a major public health problem
 Ranked 2nd by WHO to all diseases in 2010.
 Depression : a major mood disorders affecting 340 million
people worldwide
 Chronic and recurrent depression : disrupts the normal
physical & social well being , drives individual to suicide

31. Goal of treatment of MDD:
 Remission of all symptoms
 Complete recovery of social & vocational dysfunction
Rx available
 SSRIs
 SNRIs
 TCAs

32. A new drug !!…but... Y?
 TCAs –
 poor tolerability & lethargy in high dose
 Reserved for non-responders to SSRIs, SNRIs
 SSRIs
 Mild to moderate depression
 Safe in overdose & cost effective
 ADRs – discontinuation , sexual dysfunction , GI
disturbances & wt. gain. – only 30-40% achieve
remission – increased risk of relapsing , worsening of
long term prognosis

33. Pathogenesis of depression
Monoamine hypothesis :
 Depletion of monoamines in hippocampus , limbic system
& frontal cortex
 SSRIs, SNRIs , TCAs – increases monoamines – only effective
in 50% of patients.

34. Melatonin hypothesis
 New evidence – disruption of circadian rhythm –
predisposes to depression
 Melatonin – hormone from pineal gland – regulates
circadian rhythm
 Patients with depression
 Low levels of melatonin
 Delayed onset of sleep
 Difficulty in maintaining sleep
 Early morning awakening

35.  MT1 & MT2 Rs
 MT1 – acute inhibition of neuronal firing within SCN
 MT2 – induces phase shifting of circadian rhythm

36. Chemistry
 Synthetic analog of the hormone melatonin
 N-[2-(7-methoxynaphthalen-1-yl) ethyl] acetamide

37. Mechanism of action
 Synthetic analogue of human hormone melatonin
 Actions on – MT1 & MT2 Rs
 Seratonin rs antagonists (5HT-2C)
 Neurogenesis

38. Pharmacokinetics
Metabolism :
 Metabolized by Cytochrome P450 1A2 to 7-O –
demethylated and hydroxylated inactive metabolites
Excretion :
 60-80% excreted as metabolites in urine
 Metabolised to 3,4 dihydrodiol which is excreted in
faeces

39. Dosage
 25 mg / day
 Given once at bed time for 2 weeks
 Dose increased to 50 mg if response is
inadequate
 Sublingual agomelatine 0.5-2mg – under trial

40. Precautions
 Hepatic impairment - ↑plasma levels upto 100
times
 Renal impairment - ↑ plasma levels by 25 %
 Pregnancy & lactation
 Pediatric
 ≥ 60 yrs of age

41. Drug interactions
 Does not inhibit or induce Cytochrome p450
enzymes
 Enzyme inducers like omeprazole and nicotine
decrease the serum levels of agomelatine.
 Enzyme inhibitors like Fluoxamine and oestrogens
increase the serum levels

42. Uses
 Major depressive disorder especially in non-responders and
intolerant to SSRIs
 Generalized anxiety disorder
 Bipolar depression
 Sleep disturbances
 Migraine and cluster headaches

43. Adverse drug reactions
 Well tolerated
 Adverse effect profile similar to placebo
 Headache, nausea, dry mouth, fatigue
 Dizziness †
 Diarrhea / constipation
 Insomnia, somnolence
 Upper abdominal pain

44. Overdose
 Well tolerated
 Reported overdoses up to 525mg have not resulted in
significant or serious sequelae.
 1200mg was taken in earliest clinical sstudies
 800mg – maximum tolerated dose
 LD50 in animals was 100 times greater than the human
dose

45. Brands in India
Brand Name
Composi
tion Company Packing MRP Rs
AGOTINE Agomelatine 25mg UNICHEM 10 70
AGOVIZ Agomelatine 25mg ABBOTT 10 69.5
CIRCALTIN Agomelatine 25mg
ZYDUS
NEUROSCIENCE 7 49
NOVELTIN Agomelatine 25mg INTAS 10 79.5

46. Pharmacoeconomics
 Agomelatine with venlafaxine, sertraline, fluoxetine or
escitalopram
 Provides greater benefit and is less costly compared to
escitalopram, generic fluoxetine and generic sertraline
 Cost-effective alternate to generic venlafaxine

48. Advantages
 Good tolerability profile
 No discontinuation symptoms
 Serotonin syndrome, suicidal tendencies, cardiovascular
effects and weight gain have not been observed
 Minimal GI disturbance and sexual dysfunction
 Efficacy is similar to SSRIs and relapse rate is less compared
to all the other antidepressants
 Improves the quality of sleep without daytime sedation

49. Limitations
 Lack of long term active comparator controlled studies.

50. Approval status
 Europe & Australia – 2006 for major depression
 USA – yet to be approved

51. Clinical Trials
 Dose finding and efficacy study: 25mg – 50mg bed time dose
 Early onset of efficacy: Agomelatine has quick onset of action
detectable from 7th day after starting treatment as compared to
venlafaxine
 With active comparators: Agomelatine demonstrated greater
efficacy than venlafaxine and sertraline at 6 months
 Sleep and day time functioning: Agomelatine was superior to
venlafaxine and sertraline in “getting to sleep and quality of sleep”.
 Relapse and remission: Goodwin et al have shown significantly
lower relapse and remission rate vs placebo. An insignificant
difference between agomelatine and sertraline or venlafaxine was
observed
51