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![Chemistry
Synthetic analog of the hormone melatonin
N-[2-(7-methoxynaphthalen-1-yl) ethyl] acetamide](https://image.slidesharecdn.com/asenapineagomelatine-170209104220/85/Asenapine-agomelatine-36-320.jpg)
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Asenapine & agomelatine
- 1. Asenapine & Agomelatine 1 Dr.Jervin Mano, MD
- 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 ofYears 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 ofanti-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 newtreatment 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 mechanismof 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 byUGT1A4 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 5mgsublingual tablets 10 mg sublingual tablets 12
- 13.
- 14. Patient Counselling Information 1.Gentlyremove 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 comeswith 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 NeurolepticMalignant 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 Oralhypoesthesia 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 Hyperglycemiaand 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.
- 21. Asenapine And WeightGain 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 Asenapineweakly 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 adversereactions 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 Adultpatients 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 formconvinient 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.
- 30. Depression Mood disordersis 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 treatmentof 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 Monoaminehypothesis : Depletion of monoamines in hippocampus , limbic system & frontal cortex SSRIs, SNRIs , TCAs – increases monoamines – only effective in 50% of patients.
- 34. Melatonin hypothesis Newevidence – 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 analogof 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 : Metabolizedby 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 Doesnot 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 depressivedisorder 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 BrandName 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 withvenlafaxine, 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 tolerabilityprofile 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 oflong term active comparator controlled studies.
- 50. Approval status Europe& Australia – 2006 for major depression USA – yet to be approved
- 51. Clinical Trials Dosefinding 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
Editor's Notes
- #24 Neonates exposed to antipsychotic drugs during 3rd trimester of pregnancy are at risk for EPS or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU unit support and prolonged hospitalization
- #42 Other enzyme inhibitors like paroxetine, fluconazole, lithium, lorazepam, alcohol and valproic acid have insignificant interaction with Agomelatine