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Clinical profile of Valproate
 

Clinical profile of Valproate

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Different clinical aspects of valproate. Generic substitutions of AEDs

Different clinical aspects of valproate. Generic substitutions of AEDs

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    Clinical profile of Valproate Clinical profile of Valproate Presentation Transcript

    • Usage profile ofVALPROATE
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVALPROATE Most common used mood-stabilizer and antiepileptic worldwide Valproate (VPA) is a general term used to include all available forms of valproic acid, such as sodium valproate, magnesium valproate and sodium divalproex. 2
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.com VPA INCREASES GABAShiloh R, et al. Atlas of psychiatric pharmacotherapy. 2nd ed. 2006. Taylor & Francis group 3
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comIMPORTANT KINETICS ↓ CYP 2C9 4
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVPA AS A PSYCHOTROPIC BAD: Mania (euphoric, dysphoric, psychotic or rapid cycling) BAD: Mixed Good prognostic signs for valproate may include: ● Rapid cycling or dysphoric mania; ● Stable or decreasing frequency of manic exacerbations. 5
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVPA AS A PSYCHOTROPIC Augmentation to antipsychotics in schizophrenia: a common practice with limited evidence (Cochrane 2003), decreases aggression & impulsivity esp if substance induced. In Unipolar depression: (III) decreases agitation In anxiety ds: Panic (II), PTSD (II), social phobia (III), OCD (IV) In SUD: Alcohol (III) 6
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVPA IN IMPULSIVITY AND AGGRESSION 7
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.com WEAK ROLE OF VPA IN ACUTE BIPOLAR DEPRESSIONKemp D, et al. Antiepileptic Drugs in the Treatment of Rapid-Cycling Bipolar Disorder and Bipolar Depression. In: McElroy S, et al (editors). 8Antiepileptic Drugs to Treat Psychiatric Disorders. 2008. Informa Healthcare USA, Inc.
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVPA: NEUROLOGIC USE Epilepsy: broad spectrum AED Migraine: prophylaxis Neuropathic pain: weak evidence 9
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVPA DOSING 10
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comSIDE EFFECTS ESP: in children and women Tremor, sedation, fatigue, and ataxia, behavioral changes. Local GI irritation that can lead to abdominal pain, nausea, diarrhea, or constipation. Pancreatitis Thrombocytopenia and platelet dysfunction Hypertransaminases, hepatotoxicity and jaundice 11
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comSIDE EFFECTS Carnitine deficiency In women, valproate is associated with polycystic ovaries (PCO), hyperandrogenism, and weight gain. Combined with its teratogenic effects, valproate use in women of childbearing age is DONE WITH CAUTION An increase in appetite and weight gain occur in some patients; less often, anorexia and weight loss occur 12
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comVPA IN WOMEN Weight gain PCO Teratogenecity: up to 5%, esp ≥ 700 mg / d Can be used with contraception pills and during lactation 13
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comA RECENT MAULTVARIATE ANALYSIS FROMEURAPTomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, Perucca E, Vajda F; for the EURAP study group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.Lancet Neurol. 2011 Jul;10(7):609-617. Epub 2011 Jun 5. PubMed PMID: 21652013. 14
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comNEW LESSON FROM EURAP 2011“The risk of major congenital malformations is influenced not only by TYPE of antiepileptic drug, but also by DOSE AND OTHER VARIABLES.” (EURAP, 2011) 15
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comGENERIC SUBSTITUTION OF AEDS More than 100 articles in MEDLINE Generic prescribing for epilepsy remains controversial worldwide FDA and many health authorities: AGREES AAN and many epilepsy societies : DISAGREE No controlled studies, but strong anecdotal evidence, expert opinions and surveys. 16
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comGENERIC VS BRANDGeneric drug: identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.Bioequivalence: demonstration that both the rate and extent of absorption of the active ingredient of the generic drug fall within established parameters when compared to that of the reference listed drug.Office of Generic Drugs, http://www.fda.gov/cder/ogd/ 17
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comOF CONCERN AS REGARDS AEDSCrawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? Areview of issues. Seizure. 2006 Apr;15(3):165-76. Review. PubMed PMID: 16504545. 18
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comPOTENTIAL DISADVANTAGES OF GENERICMEDICINES Rate and extent of absorption (bioavailability) differs between different generic versions of branded products Generic names are not as easy to remember, spell or pronounce as branded names Generic products usually differ in appearance from the brand and from other generic versions of the same product, leading to patient confusion and anxiety Excipients and colorants used in generic products may differ from the brand, potentially causing Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A problems review of issues. Seizure. 2006 Apr;15(3):165-76. Review. PubMed PMID: 16504545. 19
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comISSUES FOR GENERICS SPECIFIC TO EPILEPSY Seriousness of BREAKTHROUGH SEIZURES. Some AEDs have narrow therapeutic index  Defined by FDA as less than two-fold difference between the minimum toxic concentration and the minimum effective concentration  Particularly true for CBZ, PHT and VPA  Individual patients may have even narrower differences between efficacy andCrawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? Areview of issues. Seizure. 2006 Apr;15(3):165-76. Review. PubMed PMID: 16504545. toxicity 20
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comWHAT ELSE? Non linear kinetics: PHT Titration: LMT Continuous change of supplier: payer / price Potential savings vs potential costs  Savings associated with a generic may be offset by costs associated with office visits, lab tests, emergency room visits or hospitalizations So, problems with SWITCH: branded to generic AED / generic to another generic. So, you must INFORM the pt ! 21
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.com CONSENSUS CLINICAL PRACTICE GUIDELINES OF THE ANDALUSIAN EPILEPSY SOCIETY ON PRESCRIBING GENERIC ANTIEPILEPTIC DRUGS (2009)  1) Not replacing an innovative AED by its generic in a CONTROLLED PATIENT  2) BEGINNING TREATMENT with a generic AED in monotherapy or in association is acceptable;  3) Not exchanging generic AED from different pharmaceutical COMPANIES  4) EXPLAINING TO THE PATIENT the rules governing the authorization of generics and the importance of avoiding exchanges between different generic AED  5) If there is some WORSENING of the clinical condition or side effects appear following the introduction of a generic, the causes must be investigated and communicated to the bodies responsible for pharmacovigilance.Cañadillas-Hidalgo FM, Sánchez-Alvarez JC, Serrano-Castro PJ, Mercadé-Cerdá JM; en representación de la SociedadAndaluza de Epilepsia. [Consensus clinical practice guidelines of the Andalusian Epilepsy Society on prescribing genericantiepileptic drugs]. Rev Neurol. 2009 Jul 1-15;49(1):41-7. Spanish. PubMed PMID: 19557699. 22
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comEXPERIENCE FROM FRANCE In France: Although no formal studies regarding cost effectiveness and the rate of seizure recurrence is available yet, the prevailing consensus recommends NOT TO REPLACE an original antiepileptic drug by a generic, due to the harmful risk of seizure recurrence.Maeder-Ingvar M, Foletti GB. [Generics of antiepileptic drugs]. Rev Med Suisse. 2010 May 5;6(247):907-9. PubMed PMID:20499577. 23
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.com EXPERIENCE FROM ITALY  LICE: The working group considered that in patients who ACHIEVED SEIZURE FREEDOM a modest change in plasma drug levels, which may occasionally occur even after substitution of products that meet bioequivalence criteria, could in rare cases lead to seizure breakthrough. Therefore, generic substitution is not recommended in patients who achieved seizure remission.  SWITCHES between a particular generic and another generic should also be preferably avoided.  Finally, SUSTAINED-RELEASE AED FORMULATIONS should not be used interchangeably with immediate- release brand or generic products.Perucca E, Albani F, Capovilla G, Bernardina BD, Michelucci R, Zaccara G. Recommendations of the Italian Leagueagainst Epilepsy working group on generic products of antiepileptic drugs. Epilepsia. 2006;47 Suppl 5:16-20. PubMedPMID: 17239100. 24
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comSUGGESTED ARTICLES Generic antiepileptic drug use was associated with significantly greater medical utilization and risk of epilepsy-related medical events, compared to brand use. This relationship was observed even in patients characterized as STABLE.Labiner DM, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latrémouille-Viau D, Lefebvre P, Helmers SL. Genericantiepileptic drugs and associated medical resource utilization in the United States. Neurology. 2010 May 18;74(20):1566-74.PubMed PMID: 20393142. 25
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comSUGGESTED ARTICLES Generics do not always lead to the anticipated MONETARY SAVINGS Desmarais JE, Beauclair L, Margolese HC. Switching from Brand-Name to Generic Psychotropic Medications: A Literature Review. CNS Neurosci Ther. 2010 Nov 30. PubMed PMID: 21114789. Significantly HIGHER HEALTH CARE COSTS were observed during generic AED use across seizure control and AED subgroups.Helmers SL, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latrémouille-Viau D, Lefebvre P, Labiner DM. Economic burdenassociated with the use of generic antiepileptic drugs in the United States. Epilepsy Behav. 2010 Aug;18(4):437-44. PubMed PMID:20580619. 26
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comSUGGESTED ARTICLES Current literature suggests statistically HIGHER OVERALL HEALTHCARE COSTS during periods of generic AED use than during periods when branded AED are used, consistently demonstrated across different countries (Canada and the USA) and in both stable and unstable epilepsy patients, with more pronounced cost increases in patients receiving multiple generic versions. Brand-to-generic substitutions of AEDs do not necessarily reduce overall healthcare costs and may even increase them.Duh MS, Cahill KE, Paradis PE, Cremieux PY, Greenberg PE. The economic implications of generic substitution of antiepilepticdrugs: a review of recent evidence. Expert Opin Pharmacother. 2009 Oct;10(14):2317-28. Review. PubMed PMID: 19663636. 27
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comSUGGESTED ARTICLES Seizure control should not be sacrificed on the basis of costs alone. choosing AED therapy solely on the basis of initial acquisition costs is unlikely to be cost effective in the long-term care of patients with epilepsy. Jobst BC, Holmes GL. Prescribing antiepileptic drugs: should patients be switched on the basis of cost? CNS Drugs. 2004;18(10):617-28. Review. PubMed PMID: 15270592. Trinka E, Krämer G, Graf M. Requirements for generic antiepileptic medicines: a clinical perspective. J Neurol. 2011 Jun 11. PubMed PMID: 21667222. Sander JW, Ryvlin P, Stefan H, Booth DR, Bauer J. Generic substitution of antiepileptic drugs. Expert Rev Neurother. 2010 Dec;10(12):1887-98. Review. PubMed PMID: 21091318. 28
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comGENERICS OF VPA IN EGYPT1. CONVULEX: Gerot 8. SEIZOLOW: Alexandria2. DAVIKEN: Amoun 9. VALPO: Unipharma3. DEKADEL: Delta 10. VALPOKINE: T3A4. DEPACOM: Chemipharm 11. VALPONEX /5. DEPAKINE: Global VALPOEAST: Napi Western6. DEPAKINE: 12. VALPROEX: MUP Sanofi-Winthrop 13. VALPROTEC:7. DEPALEPT: ACAPI Memphis Ministry of Health: EDA Index, May 2011 14. XOPLICT: Medizen 29
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comATP SURVEY, JUNE 2011 30
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comATP SURVEY, JUNE 2011 31
    • Abbasssia Training Cairo, July 2011 Program, atpbox@gmail.comATP SURVEY, JUNE 2011       32