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Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
Generic versus brand antiepileptic drugs  keppra
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Generic versus brand antiepileptic drugs keppra

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  • Aim : to stop attacks No attacks / No S/E Start with minimal dose and increase gradually Stop if side effects appeared Don’t withdraw AED suddenly but gradually Do not change cooker
  • Keppra® was previously approved in the U.S. as adjunctive therapy for partial onset seizures in adults and children four years of age and older with epilepsy.
  • Injection form
  • Formulary committees, health policy makers, consumer groups and others may see the increased use of generic products as an important tool in the battle to control healthcare costs
  • There are presently 26 different generic preparations for five brand name antiepileptic drugs(AEDs) on the Canadian market with others likely to be released in the near future
  • More available – in - More available – from-
  • The original producers of the drug bear the research and development costs while the companies producing generics also benefit despite the fact that they did not contribute to the development of that drug and in general, do little to promote new drug development.
  • Generic drugs must meet federal manufacturing standards for identity, strength, quality, purity and potency and provincial standards for clinical e q u i v a l e n c e
  • differences in non-medicinal ingredients and manufacturing process may result in variations between generic and brand name products in such factors as taste, shelf life, dissolution rate and extent, in vivo pharmacokinetics and appearance
  • Bioequivalence implies (but does not guarantee) that a drug will have the same therapeutic and adverse effects as the reference drug
  • Acceptance criteria in ministry of health The bioavailability of a generic drug is compared with that of the brand name drug by administering each as single doses to the same volunteers at different times. Approximately 12 to 18 serum samples are collected per subject per dose and a plot is made of serum concentration versus time. From this plot, a number of important pharmacokinetic parameters are calculated which measure the rate and extent of drug absorption and predict the mean steady-state serum concentration during chronic administration. It should be noted that these studies are almost always carried out in fasting, young, healthy, male adults, close to their ideal body weight, using single doses of the drug rather than in actual patients with epilepsy taking multiple doses and often multiple medications that may interact.
  • Just one seizure after a period of control can have major implications at the social level (e.g. school problem, loss of driving license, loss of employment) and at the personal level (e.g. risk of injury, loss of self-esteem, family stress ). There may even be fatal consequences–—the risk of death in patients with uncontrolled seizures is higher than in seizure-free patients There is, therefore, considerably more at stake when treating epilepsy than with many other conditions, such as peptic ulcer, when any slight loss of efficacy on changing product would be expected to have limited consequences
  • 1- Many AEDs are considered to be treatments with a narrow therapeutic index (i.e. only a small relative difference in dose between therapeutic and toxic effects). A narrow therapeutic index implies that slight variations in drug absorption could result in significant negative health outcomes. 2- The FDA considers a drug to have a narrow therapeutic index if: there is less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration; safe and effective use requires careful titration and patient monitoring 3- Even AEDs with low toxicity and with a wide therapeutic index, such as lamotrigine, require titration to the optimal dose
  • If adequate control of seizures is not achieved with a tolerable dose of one or two AEDs in sequential monotherapy, then other AEDs are often added as adjunctive therapy, again with titration according to the therapeutic response. As a result, many patients with epilepsy are on a daily regimen of multiple treatments that has been carefully adjusted to obtain the optimal response.
  • bioequivalence, as defined by regulatory bodies, may not correspond to therapeutic equivalence for AEDs, because of the permitted range of bioavailability for generics, evaluation methods that use small numbers of relatively young healthy volunteers and individual variation;
  • Furthermore, despite the lack of specific regulations concerning the excipients in a generic formulation, these substances cannot be considered inactive or inert molecules, as different salts of the same active drug can have distinct chemical and biological properties
  • The evaluation of bioequivalence in a population of patients with epilepsy is not the same as establishing bioequivalence for healthy volunteers. It is well known that patients with epilepsy respond to AEDs in different ways, so that individual titration of doses is required. Bioequivalence studies are usually carried out with single doses on small numbers of healthy volunteers (usually young adults) who are not receiving other therapies. This is done in order to eliminate factors (such as the presence of a disease state) that may cause variations in the results. In the clinical situation, patients with epilepsy often receive multiple drugs. Many patients are likely to be older or younger than the adults used in standard tests, with consequent differences in drug handling characteristics. Some commentators have raised concerns about the accepted methods for evaluating bioequivalence
  • Once a number of generic products are on the market, pharmacists may change their supplier according to price and availability. A patient stabilised on one AED may be at risk of that control being lost if the prescription is changed to a formulation from a different manufacturer. In the USA, the FDA has used the term prescribability to describe the use of a generic as first therapy, and the term switchability for the use of a generic in a patient already established on therapy
  • Either as a starting or as changing The question arises of legal responsibility if a breakthrough seizure occurs when the medication a patient has previously received is changed for another
  • Critical disease: Intercurrent disorders, mainly in chronic care, where drug-disease interactions present major problems, those with serious clinical sequelae, should therapy fail Critical drugs: Narrow therapeutic index, those requiring a complex therapeutic regimen, those with considerable drug interactions, those requiring titration of individual doses
  • In Denmark, some AEDs containing oxcarbamazepine are exempt from generic substitution \\because of bioequivalence problems 2006 add gabapentin as new drug with old low theurapeutic indexes drugs
  • Recur szs or increase szs Although newer AEDs, such as lamotrigine, gabapentin, topiramate and levetriacetam, are not considered to have a narrow therapeutic range like carbamazepine or valproate, some of the issues of concern still apply. Like the older AEDs,they require individual titration, and the consequences of a breakthrough seizure are the same, regardless of the therapy that failed
  • Widespread recognition exists that certain medications are not interchangeable. This mandate has been applied to some commonly used drugs including digoxin and warfarin.
  • The following risk factors for problems with generic substitution apply to certain antiepileptic drugs: low water solubility (PHT & CBZ); non-linear pharmacokinetics (PHT and valproate [VPA]); and narrow therapeutic range (PHT, CBZ & VPA). Antiepileptic drugs, such as phenytoin (PHT) and carbamazepine (CBZ), have long been recognized as drugs which should not be substituted because of their narrow therapeutic index and pharmacologic properties.3 , 5 C a r b a m a z e p i n e , phenytoin and valproate are listed as narrow therapeutic index drugs by the FDA and there are seven states which restrict the substitution of one or more of these drugs
  • Apart from pharmacokinetic considerations, antiepileptic drugs are generally used to treat a potentially serious condition. Unexpected breakthrough seizures in a controlled patient could lead to adverse psychosocial consequences such as loss of job or driver’s licence, physical injury or, rarely, death. In a controlled epileptic patient who is driving, an unexpected seizure could also endanger pedestrians or other motorists
  • Although newer antiepileptic drugs such as lamotrigine, vigabatrin, gabapentin and topiramate are not considered to have a narrow therapeutic range, the relationship of plasma concentration to their clinical effects has not yet been fully e s t a b l i s h e d
  • British Epilepsy Association survey found that 46.5% of people perceived a deterioration in their condition after being switched to a different supply of the same AED.
  • Use of generic products may inhibit research and innovation
  • The original manufacturer may apply for many patents: for the chemical, different dosage forms or strengths and even the manufacturing process, and each generic manufacturer must determine if enough of the important patents have expired to make it worthwhile to market a particular drug.
  • Transcript

    • 1. Generic Substitution for Brand Name Antiepileptic Drugs Prof Dr Hussein Abdeldayem. MD Chief of Pediatric Neurology Unit Faculty Medicine, Alex University
    • 2. Practical points
      • Stop attacks with no S/E
      • Start with minimal dose
      • duration : 2years from last attack
      • withdraw slowly for 6 months
      • DON’T CHANGE COOKER
      Treatment
    • 3. Practical Implications
      • CBZ,
      • Oxcarbazepine
      • LMT
      • Phenytoin
      • Gabapentin
      • May not work or may even exacerbate myoclonic seizures
    • 4. Practical Implications –cont.
      • CBZ,
      • oxcarbazepine
      • Phenytoin
      • Gabapentin
      • May not work or may even exacerbate absence seizures
    • 5. GENERALIZED FITS PARTIAL FITS Focal with 2ry generalization FITS Absence – Myoclonic - IS
    • 6. KEPPRA GENERALIZED FITS PARTIAL FITS
    • 7.
      • 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)
    • 8. FDA approval for Keppra in infants and children from one month of age with partial onset seizures January 26, 2012
    • 9. 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
    • 10. Generic Substitution for Brand Name Antiepileptic Drugs Prof Dr Hussein Abdeldayem, MD
    • 11. In response to increasing cost pressures, healthcare systems are encouraging the use of generic medicines.
    • 12.
      • The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years.
    • 13.  
    • 14. Benefits
      • Reduction of treatment costs
      assessed the risk/benefit ratio of generic substitution.
    • 15. 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)
    • 16. Generic drug Same
      • same qualitative and quantitative composition in terms of active substances,
      • same pharmaceutical form,
      • Same strength,
      • same route of administration, and
      • Equivalent bioavailability (bioequivalence).
    • 17. Generic drug Not 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.
    • 18. 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, .
    • 19. ARE GENERIC AND BRAND NAME AEDS EQUIVALENT?
      • Control group
      • Method:
      • - Single doses
      • - 12 – 18 serum samples/dose
      • Results:
      • TIME/CONCENTRATION
    • 20. 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
    • 21. 1- Characteristics of epilepsy
      • seriousness of therapy failure
      • social level
      • personal level
      • self health/life
    • 22. 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
    • 23. 3- Complexity of management regimens
      • Establishing seizure control can be difficult,
      • need for slow titration,
      • drug interactions
    • 24. 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
    • 25. 4- PLUS
      • Excipients cannot be considered inactive or inert molecules
    • 26. 5-Evaluation of bioequivalence Individual variation
      • Epileptic patients vz non epileptic patients
      • Polytherapy AEDs
      • Age differences
      the American Academy of Neurology noted that the ratio of generic to branded bioavailability in individual subjects reported to the FDA varied from 74% to 142%.
    • 27. 6- Continuity of supply
      • Switchability (FDA)
      • Insurance service / pharmacists
    • 28. 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.
    • 29. 8- Legal situation
      • The question arises of legal responsibility if a breakthrough seizure occurs
    • 30. CLINICAL EXPERIENCE
      • Experience with generic substitution of
      • VPA
      • Keppra
    • 31. 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,
    • 32. Special categories proposed for exemption from mandatory generic substitution
      • Critical diseases
      • Critical drugs
      • Epilepsy
      • AED
    • 33. 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
    • 34. 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
    • 35. 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
    • 36. 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
    • 37.
      • Omayma 0233051307
    • 38. USE OF GENERICS IN EPILEPTIC PATIENTS
      • Widespread recognition exists that certain medications are not interchangeable.
    • 39. 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).
    • 40. USE OF GENERICS IN EPILEPTIC PATIENTS
      • AEDs are used to treat a potential serious condition
      • Usage duration
      • S E
      • Normal Life
      • Parents stress
    • 41. 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
      • .
    • 42. 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
    • 43. 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
    • 44. 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
    • 45. Potential problems with generic substitution included:
    • 46. Potential problems
      • potentially serious consequences of failure of therapy, particularly in well-controlled patients
    • 47. Potential problems
      • potential for adverse events and variability of response to AEDs
    • 48. 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
    • 49. Potential problems
      • potential for problems from poor continuity of supply
      • cost savings may be outweighed by the cost of adverse consequences;
    • 50. 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
    • 51. 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
    • 52. 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
    • 53. 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
    • 54.
      • The German Section of the International League against Epilepsy requested that AEDs be excluded from regulations allowing “automatic” substitution of brand products with generics
    • 55.
      • 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.”
    • 56.
      • 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).
    • 57.
      • 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.
    • 58. CONSIDERATIONS
    • 59. 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
    • 60. 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
    • 61. 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
    • 62. 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)
    • 63. 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
    • 64. 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

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