Valproate Usage and Safety Profile in 40 Characters

Abbasssia Training Cairo, July 2011
Program, atpbox@gmail.com

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

Shiloh R, et al. Atlas of psychiatric pharmacotherapy. 2nd ed. 2006. Taylor & Francis group 3


IMPORTANT KINETICS

 ↓ CYP 2C9

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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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VPA IN IMPULSIVITY AND AGGRESSION

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WEAK ROLE OF VPA IN ACUTE BIPOLAR
DEPRESSION

Kemp D, et al. Antiepileptic Drugs in the Treatment of Rapid-Cycling Bipolar Disorder and Bipolar Depression. In: McElroy S, et al (editors). 8
Antiepileptic Drugs to Treat Psychiatric Disorders. 2008. Informa Healthcare USA, Inc.


VPA: NEUROLOGIC USE

 Epilepsy: broad spectrum AED
 Migraine: prophylaxis

 Neuropathic pain: weak evidence

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VPA DOSING

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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

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

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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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 20


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.
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.

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.

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.
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
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 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.
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.
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.

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GENERICS OF VPA IN EGYPT
1. CONVULEX: Gerot 8. SEIZOLOW:
Alexandria
2. DAVIKEN: Amoun
9. VALPO: Unipharma
3. DEKADEL: Delta
10. VALPOKINE: T3A
4. DEPACOM:
Chemipharm 11. VALPONEX /
5. DEPAKINE: Global VALPOEAST:
Napi Western

6. DEPAKINE: 12. VALPROEX: MUP
Sanofi-Winthrop 13. VALPROTEC:
7. DEPALEPT: ACAPI
Memphis
Ministry of Health: EDA Index, May 2011 14. XOPLICT: Medizen
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ATP SURVEY, JUNE 2011

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