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Different clinical aspects of valproate. Generic substitutions of AEDs
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VALPROATEUsage profile of
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VALPROATE
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.
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VPA INCREASES GABA
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Shiloh R, et al. Atlas of psychiatric pharmacotherapy. 2nd ed. 2006. Taylor & Francis group
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VPA 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.
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VPA 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)
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WEAK ROLE OF VPA IN ACUTE BIPOLAR DEPRESSION
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Kemp D, et al. Antiepileptic Drugs in the Treatment of Rapid-Cycling Bipolar Disorder and Bipolar Depression. In: McElroy S, et al (editors). Antiepileptic Drugs to Treat Psychiatric Disorders. 2008. Informa Healthcare USA, Inc.
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VPA: NEUROLOGIC USE
Epilepsy: broad spectrum AED Migraine: prophylaxis Neuropathic pain: weak evidence
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SIDE 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
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SIDE 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
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VPA IN WOMEN
Weight gain PCO Teratogenecity: up to 5%, esp ≥ 700
mg / d Can be used with contraception pills
and during lactation
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A RECENT MAULTVARIATE ANALYSIS FROM EURAP
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Tomson 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.
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NEW 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)
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GENERIC 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.
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GENERIC VS BRAND
Generic 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/
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OF CONCERN AS REGARDS AEDS
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Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006 Apr;15(3):165-76. Review. PubMed PMID: 16504545.
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POTENTIAL DISADVANTAGES OF GENERIC MEDICINES
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 problems
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Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006 Apr;15(3):165-76. Review. PubMed PMID: 16504545.
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ISSUES 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 and toxicity
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Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006 Apr;15(3):165-76. Review. PubMed PMID: 16504545.
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WHAT 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 !
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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.
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Cañadillas-Hidalgo FM, Sánchez-Alvarez JC, Serrano-Castro PJ, Mercadé-Cerdá JM; en representación de la Sociedad Andaluza de Epilepsia. [Consensus clinical practice guidelines of the Andalusian Epilepsy Society on prescribing generic antiepileptic drugs]. Rev Neurol. 2009 Jul 1-15;49(1):41-7. Spanish. PubMed PMID: 19557699.
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EXPERIENCE 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.
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Maeder-Ingvar M, Foletti GB. [Generics of antiepileptic drugs]. Rev Med Suisse. 2010 May 5;6(247):907-9. PubMed PMID: 20499577.
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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.
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Perucca E, Albani F, Capovilla G, Bernardina BD, Michelucci R, Zaccara G. Recommendations of the Italian League against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia. 2006;47 Suppl 5:16-20. PubMed PMID: 17239100.
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SUGGESTED 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.
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Labiner DM, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latrémouille-Viau D, Lefebvre P, Helmers SL. Generic antiepileptic drugs and associated medical resource utilization in the United States. Neurology. 2010 May 18;74(20):1566-74. PubMed PMID: 20393142.
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SUGGESTED ARTICLES
Generics do not always lead to the anticipated MONETARY SAVINGS
Significantly HIGHER HEALTH CARE COSTS were observed during generic AED use across seizure control and AED subgroups.
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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.
Helmers SL, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latrémouille-Viau D, Lefebvre P, Labiner DM. Economic burden associated with the use of generic antiepileptic drugs in the United States. Epilepsy Behav. 2010 Aug;18(4):437-44. PubMed PMID: 20580619.
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SUGGESTED 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.
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Duh MS, Cahill KE, Paradis PE, Cremieux PY, Greenberg PE. The economic implications of generic substitution of antiepileptic drugs: a review of recent evidence. Expert Opin Pharmacother. 2009 Oct;10(14):2317-28. Review. PubMed PMID: 19663636.
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SUGGESTED 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.
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.
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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.
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GENERICS OF VPA IN EGYPT
1. CONVULEX: Gerot 2. DAVIKEN: Amoun 3. DEKADEL: Delta
4. DEPACOM: Chemipharm
5. DEPAKINE: Global Napi
6. DEPAKINE: Sanofi-Winthrop
7. DEPALEPT: Memphis
8. SEIZOLOW: Alexandria
9. VALPO: Unipharma 10. VALPOKINE: T3A 11. VALPONEX /
VALPOEAST: Western
12. VALPROEX: MUP
13. VALPROTEC: ACAPI 14. XOPLICT: Medizen
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Ministry of Health: EDA Index, May 2011
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ATP SURVEY, JUNE 2011
صرعية نوبات حدوث من المرضى بعض اشتكىأخرى مرة
اندفاع أعراض ظهور من المرضى بعض اشتكى الدواء على للحكم كافية غير الفترة العالج نوع تغيير بعد مستقر غير طفل حالة كبرى مستمرة تشنجات حالة تغييرها وعدم ممتازة شركة من الصرع أدوية تثبيت
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