Asenapine & Agomelatine

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Dr. Jervin Mano, MD

Asenapine

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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

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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%

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Past historic of anti-psychotics : 5

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

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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

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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

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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

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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%)

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TRADE NAME & COST

US/EUROPE

Saphris, Sycrest

INDIA

Asenapt marketed by Sun pharmaceuticals

5mg 10 tabs - ₹55

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DOSAGE FORMS

5mg sublingual tablets

10 mg sublingual tablets

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INDICATIONS & DOSAGES 13

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.

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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

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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

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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

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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

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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

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Extrapyramidal Reactions 20

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Dyskinesia Akathisia Parkinsonism

Patient Percentage (%)

Asenapine And Weight GainShort-term trial

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0

0,5

1

1,5

2

2,5

3

Placebo All Asenapine (5-

10mg BID)Olanzapine (5-20mg

QD)Risperidone (3mg

BID)

Mean Change from Baseline Body Weight (Kg)

Placebo

All Asenapine (5-10mg BID)

Olanzapine (5-20mg QD)

Risperidone (3mg BID)

Baseline (kg):

P=81.7

A=78.5

R=86.8

O=78.4

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Drug Interactions

Asenapine weakly inhibits CYP2D6.

Should be coadministered cautiously with drugs that are both substrates and inhibitors for CYP2D6

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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

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.

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 OneThis 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 TwoThis 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 ThreeAsenapine could not be distinguished from placebo

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

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

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, ShahidM Asenapine effects in animal models of psychosis and cognitive function. Psychopharmacology 2009 May 22

Agomelatine

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

Goal of treatment of MDD: Remission of all symptoms

Complete recovery of social & vocational dysfunction

Rx available SSRIs

SNRIs

TCAs

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

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.

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

MT1 & MT2 Rs

MT1 – acute inhibition of neuronal firing within SCN

MT2 – induces phase shifting of circadian rhythm

Chemistry

Synthetic analog of the hormone melatonin

N-[2-(7-methoxynaphthalen-1-yl) ethyl] acetamide

Mechanism of action

Synthetic analogue of human hormone melatonin

Actions on – MT1 & MT2 Rs

Seratonin rs antagonists (5HT-2C)

Neurogenesis

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

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

Precautions

Hepatic impairment - ↑plasma levels upto 100 times

Renal impairment - ↑ plasma levels by 25 %

Pregnancy & lactation

Pediatric

≥ 60 yrs of age

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

Uses

Major depressive disorder especially in non-responders and intolerant to SSRIs

Generalized anxiety disorder

Bipolar depression

Sleep disturbances

Migraine and cluster headaches

Adverse drug reactions

Well tolerated

Adverse effect profile similar to placebo

Headache, nausea, dry mouth, fatigue

Dizziness †

Diarrhea / constipation

Insomnia, somnolence

Upper abdominal pain

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

Brands in India

Brand NameComposition Company Packing MRP Rs

AGOTINE Agomelatine 25mg UNICHEM 10 70

AGOVIZ Agomelatine 25mg ABBOTT 10 69.5

CIRCALTIN Agomelatine 25mgZYDUS NEUROSCIENCE 7 49

NOVELTIN Agomelatine 25mg INTAS 10 79.5

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

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

Limitations

Lack of long term active comparator controlled studies.

Approval status

Europe & Australia – 2006 for major depression

USA – yet to be approved

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

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