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Generic Substitution for Brand Name Antiepileptic Drugs
Prof Dr Hussein Abdeldayem. MD
Chief of Pediatric Neurology Unit
Faculty Medicine, Alex University
Practical points
Stop attacks with no S/EStop attacks with no S/E Start with minimal dose Start with minimal dose duration : 2years from last attackduration : 2years from last attack withdraw slowly for 6 monthswithdraw slowly for 6 months DON’T CHANGE COOKERDON’T CHANGE COOKER
TreatmentTreatment
Practical Implications
CBZ, Oxcarbazepine LMT Phenytoin Gabapentin
May not work or may even exacerbate myoclonic seizures
Practical Implications –cont.
CBZ, oxcarbazepine Phenytoin Gabapentin
May not work or may even exacerbate absence seizures
GENERALIZED FITS
PARTIAL FITS
Focal with 2ry generalization FITS
Absence – Myoclonic - IS
KEPPRA
GENERALIZED FITS PARTIAL FITS
20 – 60 mg/kg/d Twice Forms:
Oral: (100mg/1ml)
250 mg tablets
500 mg tablets
Blood Follow up: NONE Onset of action Add on, no drug interaction
* Not before 4 years age
Keppra (Levetiracetam)
FDA approval for Keppra in infants and children from one month of age with partial onset seizures
January 26, 2012
Keppra® indications
In the U.S, European Union
1- adjunctive therapy in the treatment of partial onset seizures in adults and children one month of age and older with epilepsy, myoclonic seizures
2- as monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy
Generic Substitution for Brand NameAntiepileptic Drugs
Prof Dr Hussein Abdeldayem, MD
In response to increasing cost pressures, healthcare systems are encouragingthe use of generic medicines.
The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years.
Benefits
Reduction of treatment costs
assessed the risk/benefit ratio of generic substitution.
Generic Drug
A generic is a pharmaceutical product which is marketed under the International Non-proprietary Name (INN) and meets internationally standardized requirements for “essential similarity” to the originator’s product (henceforth called “brand” or “proprietary” product)
Generic drugSame
same qualitative and quantitative composition in terms of active substances,
same pharmaceutical form, Same strength, same route of administration, and Equivalent bioavailability (bioequivalence).
Generic drugNot like
A generic drug contains identical amounts of the same medicinal ingredient(s) as the original brand name drug, in a comparable dosage form, but does not necessarily contain the same non-medicinal ingredients.
BIOEQUIVALENT
If the generic and brand name products have :
1- the same form
2- contain the same dose of the same active ingredient(s), and
3- have similar pharmacokinetic profiles,.
ARE GENERIC AND BRAND NAME AEDS EQUIVALENT?
Control group
Method:
- Single doses
- 12 – 18 serum samples/dose
Results:- TIME/CONCENTRATION
Characteristics of epilepsy
Epilepsy is a chronic disorder that requires chronic (?) AED treatment.
Avoidance of seizures is the primary goal, while keeping adverse effects to a minimum. When long-term remission has been
achieved, it becomes important to avoid even a single breakthrough seizure
1- Characteristics of epilepsy
seriousness of therapy failure
social level
personal level
self health/life
2- Characteristics of antiepileptic drugs
narrow therapeutic index,:
“ there is less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration
potential for adverse events, individual variation in response
3- Complexity of management regimens
Establishing seizure control can be difficult, need for slow titration, drug interactions
4- Potential problems
bioequivalence may not correspond to therapeutic equivalence for AEDs
Rate and extent of absorption (bioavailability) may differ between generics and branded products
The FDA requires the generic medication produce bloodstream levels in the range of
80-125% of the level produced by the comparable brand-name medication
4- PLUS
Excipients cannot be considered inactive or inert molecules
5-Evaluation of bioequivalence Individual variation
Epileptic patients vz non epileptic patients
Polytherapy AEDs Age differences
the American Academy of Neurologynoted that the ratio of generic to branded
bioavailability in individual subjects reported to
the FDA varied from 74% to 142%.
6- Continuity of supply
Switchability (FDA) Insurance service / pharmacists
7- Economic value
The true cost of generic prescribing must also include the cost of additional visits to a physician or the hospital if the substitution causes problems, and the cost of treatment failure, if a seizure occurs.
8- Legal situation
The question arises of legal responsibility if a breakthrough seizure occurs
CLINICAL EXPERIENCE
Experience with generic substitution of
VPA
Keppra
Special categories proposed for exemption from mandatory generic substitution
Critical patients Very young, very old, those suffering from multiple diseases, those treating with poly therapy,
Special categories proposed for exemption from mandatory generic substitution
Critical diseases
Critical drugs
Epilepsy
AED
products with restrictions on generic substitution
USA-FDA : carbamazepine, phenytoin and
valproate, LVT . Spain : CBZ , gabapentin Denmark: Oxycarbamazepine Finland: All AEDs South Africa: DPH, CBZ UK: brand name prescribing for AEDs is
recommended. Sweden : CBZ, VPA, gabapentin
Seizure (2006) 15, 165—176
FDA to Tighten Standards for Generic Antiepileptic Drugs
Patients receiving levetiracetam or lamotrigine, had the highest switchback rate from generic to brand-name products
American Epilepsy Society (AES) 65th Annual Meeting Dec 2011
Conclusion
Patients with epilepsy may have a higher risk of seizures if they switch from their brand-name medication to generic anti-epileptic drugs (AEDs).
Although generic AEDs are lower in price, possible increased side effects and morbidity and the need for closer monitoring could partially offset the cost savings
References
Seizure (2006) 15, 165—176: Are there potential problems with generic substitution of antiepileptic drugs? A review of issues
Can. J. Neurol. Sci. 2000; 27: 37-43 . Generic Substitution for Brand Name Antiepileptic Drugs: A Survey
Epilepsia, 47(Suppl. 5):16–20, 2006. Recommendations of the Italian League Against Epilepsy Working Group on Generic Products of Antiepileptic Drugs
Omayma 0233051307
USE OF GENERICS IN EPILEPTIC PATIENTS
Widespread recognition exists that certain medications are not interchangeable.
USE OF GENERICS IN EPILEPTIC PATIENTS
Pharmakokinetic Consideration low water solubility (PHT & CBZ); non-linear pharmacokinetics (PHT and
valproate [VPA]); narrow therapeutic range (PHT, CBZ &
VPA).
USE OF GENERICS IN EPILEPTIC PATIENTS
AEDs are used to treat a potential serious condition
Usage duration S E Normal Life Parents stress
USE OF GENERICS IN EPILEPTIC PATIENTS
Theoretically, if patients are switched from one formulation to another, they could experience swings in plasma concentration of almost 50% Usage duration
.
USE OF GENERICS IN EPILEPTIC PATIENTS
LVT does not have a narrow therapeutic range, the relationship of plasma concentration to their clinical effects has not yet been fully
USE OF GENERICS IN EPILEPTIC PATIENTS
changes in drug blood levels may occur if a patient is switched from one company’s preparation to another
USE OF GENERICS IN EPILEPTIC PATIENTS
Several published reports have noted an increase in toxicity/deterioration upon switching to a different formulation of an AED
Tyrer JH, Eadie MJ, Sutherland JM, Hooper WD. Outbreak of anticonvulsant intoxication in an Australian city. Br Med J 1970
Potentialproblems with generic substitution included:
Potential problems
potentially serious consequences of failure of therapy, particularly in well-controlled patients
Potential problems
potential for adverse events and variability of response to AEDs
Potential problems
need for careful titration and dosing of AEDs and susceptibility of some patients to develop problems, even with small changes in drug levels
Potential problems
potential for problems from poor continuity of supply
cost savings may be outweighed by the cost of adverse consequences;
Potential problems
Generic names are not as easy to remember, spell or pronounce as branded names
Generic products usually differ in appearance (e.g. colour, shape) from the brand and from one another, causing confusion and anxiety for patients
Potential problems
Excipients and colorants used in generic products may differ from the brand–—although these agents are intended to be inert, they can cause problems in some patients
Potential problems
If problems occur with a generic product, it may be difficult to identify the manufacturer or supplier, once it has been dispensed, and the innovator company may be the recipient of the pharmacovigilance report rather than the generic company
RECOMMONDATIONS
The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (1990) advises against substituting pharmaceutical products, particularly in the case of phenytoin and CBZ
The German Section of the International League against Epilepsy requested that AEDs be excluded from regulations allowing “automatic” substitution of brand products with generics
The committee responsible for the guidelines published by the U.K. National Institute for Clinical Excellence (2004a,b) “did not consider that it had adequate evidence to make recommendations on the use of generic products in the treatment of epilepsy.”
The guidelines of the Scottish Intercollegiate Guidelines Network (SIGN) for the treatment of epilepsies in adults state that “formulations of AEDs are not interchangeable and generic substitution should not be employed” (Scottish Intercollegiate Guidelines Network, 2003).
Generic drugs can be marketed after 20 years from the time the patent is first applied for in Canada, which may precede the actual release of the drug to market by several years.
CONSIDERATIONS
FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)
CONSIDERING THAT even small variations in concentration
between name-brand and generic drugs, or from generic to generic, may induce toxic effects or favour the recurrence of seizures
FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)
CONSIDERING THAT epilepsy differs from other chronic disorders,
by the fact that a single epileptic seizure may have serious and even irreversible physical and/or socio-professional consequences
FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)
CONSIDERING THAT Most AEDs have a narrow therapeutic index,
i.e., their therapeutic dose is often close to the dose that causes toxicity
several surveys in different countries, and particularly in France
FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)
CONSIDERING THAT the studies allowing the generic drugs to be
licensed do not prove their equivalence, in terms of efficacy or tolerance, with the name-brand AEDs (lack of evidence-based data)
FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)
CONSIDERING THAT the antiepileptic drugs constitute a particular
class of drugs which makes problematic their substitution when they are used in this indication
FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)
RECOMMENDS not to substitute by generics (and even more
one generic by another) in the treatment of epilepsy, especially in patients with well controlled epilepsy