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Generic versus brand antiepileptic drugs keppra

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Generic versus brand antiepileptic drugs keppra

  1. 1. Generic Substitution for Brand Name Antiepileptic Drugs Prof Dr Hussein Abdeldayem. MD Chief of Pediatric Neurology Unit Faculty Medicine, Alex University
  2. 2. Practical points <ul><li>Stop attacks with no S/E </li></ul><ul><li>Start with minimal dose </li></ul><ul><li>duration : 2years from last attack </li></ul><ul><li>withdraw slowly for 6 months </li></ul><ul><li>DON’T CHANGE COOKER </li></ul>Treatment
  3. 3. Practical Implications <ul><li>CBZ, </li></ul><ul><li>Oxcarbazepine </li></ul><ul><li>LMT </li></ul><ul><li>Phenytoin </li></ul><ul><li>Gabapentin </li></ul><ul><li>May not work or may even exacerbate myoclonic seizures </li></ul>
  4. 4. Practical Implications –cont. <ul><li>CBZ, </li></ul><ul><li>oxcarbazepine </li></ul><ul><li>Phenytoin </li></ul><ul><li>Gabapentin </li></ul><ul><li>May not work or may even exacerbate absence seizures </li></ul>
  5. 5. GENERALIZED FITS PARTIAL FITS Focal with 2ry generalization FITS Absence – Myoclonic - IS
  6. 6. KEPPRA GENERALIZED FITS PARTIAL FITS
  7. 7. <ul><li>20 – 60 mg/kg/d </li></ul><ul><li>Twice </li></ul><ul><li>Forms: </li></ul><ul><li>Oral: (100mg/1ml) </li></ul><ul><li>250 mg tablets </li></ul><ul><li>500 mg tablets </li></ul><ul><li>Blood Follow up: NONE </li></ul><ul><li>Onset of action </li></ul><ul><li>Add on, no drug interaction </li></ul><ul><li>* Not before 4 years age </li></ul>Keppra (Levetiracetam)
  8. 8. FDA approval for Keppra in infants and children from one month of age with partial onset seizures January 26, 2012
  9. 9. Keppra® indications  <ul><li>In the U.S, European Union </li></ul><ul><li>1- adjunctive therapy in the treatment of partial onset seizures in adults and children one month of age and older with epilepsy, myoclonic seizures </li></ul><ul><li>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 </li></ul>
  10. 10. Generic Substitution for Brand Name Antiepileptic Drugs Prof Dr Hussein Abdeldayem, MD
  11. 11. In response to increasing cost pressures, healthcare systems are encouraging the use of generic medicines.
  12. 12. <ul><li>The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years. </li></ul>
  13. 14. Benefits <ul><li>Reduction of treatment costs </li></ul>assessed the risk/benefit ratio of generic substitution.
  14. 15. Generic Drug <ul><li>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) </li></ul>
  15. 16. Generic drug Same <ul><li>same qualitative and quantitative composition in terms of active substances, </li></ul><ul><li>same pharmaceutical form, </li></ul><ul><li>Same strength, </li></ul><ul><li>same route of administration, and </li></ul><ul><li>Equivalent bioavailability (bioequivalence). </li></ul>
  16. 17. Generic drug Not like <ul><li>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. </li></ul>
  17. 18. BIOEQUIVALENT <ul><li>If the generic and brand name products have : </li></ul><ul><li>1- the same form </li></ul><ul><li>2- contain the same dose of the same active ingredient(s), and </li></ul><ul><li>3- have similar pharmacokinetic profiles, . </li></ul>
  18. 19. ARE GENERIC AND BRAND NAME AEDS EQUIVALENT? <ul><li>Control group </li></ul><ul><li>Method: </li></ul><ul><li>- Single doses </li></ul><ul><li>- 12 – 18 serum samples/dose </li></ul><ul><li>Results: </li></ul><ul><li>TIME/CONCENTRATION </li></ul>
  19. 20. Characteristics of epilepsy <ul><li>Epilepsy is a chronic disorder that requires chronic (?) AED treatment. </li></ul><ul><li>Avoidance of seizures is the primary goal, </li></ul><ul><li>while keeping adverse effects to a minimum. </li></ul><ul><li>When long-term remission has been achieved, it becomes important to avoid even a single breakthrough seizure </li></ul>
  20. 21. 1- Characteristics of epilepsy <ul><li>seriousness of therapy failure </li></ul><ul><li>social level </li></ul><ul><li>personal level </li></ul><ul><li>self health/life </li></ul>
  21. 22. 2- Characteristics of antiepileptic drugs <ul><li>narrow therapeutic index,: </li></ul><ul><li>“ there is less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration </li></ul><ul><li>potential for adverse events, </li></ul><ul><li>individual variation in response </li></ul>
  22. 23. 3- Complexity of management regimens <ul><li>Establishing seizure control can be difficult, </li></ul><ul><li>need for slow titration, </li></ul><ul><li>drug interactions </li></ul>
  23. 24. 4- Potential problems <ul><li>bioequivalence may not correspond to therapeutic equivalence for AEDs </li></ul><ul><li>Rate and extent of absorption (bioavailability) may differ between generics and branded products </li></ul>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
  24. 25. 4- PLUS <ul><li>Excipients cannot be considered inactive or inert molecules </li></ul>
  25. 26. 5-Evaluation of bioequivalence Individual variation <ul><li>Epileptic patients vz non epileptic patients </li></ul><ul><li>Polytherapy AEDs </li></ul><ul><li>Age differences </li></ul>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%.
  26. 27. 6- Continuity of supply <ul><li>Switchability (FDA) </li></ul><ul><li>Insurance service / pharmacists </li></ul>
  27. 28. 7- Economic value <ul><li>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. </li></ul>
  28. 29. 8- Legal situation <ul><li>The question arises of legal responsibility if a breakthrough seizure occurs </li></ul>
  29. 30. CLINICAL EXPERIENCE <ul><li>Experience with generic substitution of </li></ul><ul><li>VPA </li></ul><ul><li>Keppra </li></ul>
  30. 31. Special categories proposed for exemption from mandatory generic substitution <ul><li>Critical patients </li></ul><ul><li>Very young, very old, those suffering from multiple diseases, those treating with poly therapy, </li></ul>
  31. 32. Special categories proposed for exemption from mandatory generic substitution <ul><li>Critical diseases </li></ul><ul><li>Critical drugs </li></ul><ul><li>Epilepsy </li></ul><ul><li>AED </li></ul>
  32. 33. products with restrictions on generic substitution <ul><li>USA-FDA : carbamazepine, phenytoin and valproate, LVT . </li></ul><ul><li>Spain : CBZ , gabapentin </li></ul><ul><li>Denmark: Oxycarbamazepine </li></ul><ul><li>Finland: All AEDs </li></ul><ul><li>South Africa: DPH, CBZ </li></ul><ul><li>UK: brand name prescribing for AEDs is recommended. </li></ul><ul><li>Sweden : CBZ, VPA, gabapentin </li></ul>Seizure (2006) 15, 165—176
  33. 34. FDA to Tighten Standards for Generic Antiepileptic Drugs <ul><li>Patients receiving levetiracetam or lamotrigine, had the highest switchback rate from generic to brand-name products </li></ul>American Epilepsy Society (AES) 65th Annual Meeting Dec 2011
  34. 35. Conclusion <ul><li>Patients with epilepsy may have a higher risk of seizures if they switch from their brand-name medication to generic anti-epileptic drugs (AEDs).  </li></ul><ul><li>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 </li></ul>
  35. 36. References <ul><li>Seizure (2006) 15, 165—176: Are there potential problems with generic substitution of antiepileptic drugs? A review of issues </li></ul><ul><li>Can. J. Neurol. Sci. 2000; 27: 37-43 . Generic Substitution for Brand Name Antiepileptic Drugs: A Survey </li></ul><ul><li>Epilepsia, 47(Suppl. 5):16–20, 2006. Recommendations of the Italian League Against Epilepsy Working Group on Generic Products of Antiepileptic Drugs </li></ul>
  36. 37. <ul><li>Omayma 0233051307 </li></ul>
  37. 38. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>Widespread recognition exists that certain medications are not interchangeable. </li></ul>
  38. 39. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>Pharmakokinetic Consideration </li></ul><ul><li>low water solubility (PHT & CBZ); </li></ul><ul><li>non-linear pharmacokinetics (PHT and valproate [VPA]); </li></ul><ul><li>narrow therapeutic range (PHT, CBZ & VPA). </li></ul>
  39. 40. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>AEDs are used to treat a potential serious condition </li></ul><ul><li>Usage duration </li></ul><ul><li>S E </li></ul><ul><li>Normal Life </li></ul><ul><li>Parents stress </li></ul>
  40. 41. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>Theoretically, if patients are switched from one formulation to another, they could experience swings in plasma concentration of almost 50% Usage duration </li></ul><ul><li>. </li></ul>
  41. 42. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>LVT does not have a narrow therapeutic range, the relationship of plasma concentration to their clinical effects has not yet been fully </li></ul>
  42. 43. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>changes in drug blood levels may occur if a patient is switched from one company’s preparation to another </li></ul>
  43. 44. USE OF GENERICS IN EPILEPTIC PATIENTS <ul><li>Several published reports have noted an increase in toxicity/deterioration upon switching to a different formulation of an AED </li></ul>Tyrer JH, Eadie MJ, Sutherland JM, Hooper WD. Outbreak of anticonvulsant intoxication in an Australian city. Br Med J 1970
  44. 45. Potential problems with generic substitution included:
  45. 46. Potential problems <ul><li>potentially serious consequences of failure of therapy, particularly in well-controlled patients </li></ul>
  46. 47. Potential problems <ul><li>potential for adverse events and variability of response to AEDs </li></ul>
  47. 48. Potential problems <ul><li>need for careful titration and dosing of AEDs and susceptibility of some patients to develop problems, even with small changes in drug levels </li></ul>
  48. 49. Potential problems <ul><li>potential for problems from poor continuity of supply </li></ul><ul><li>cost savings may be outweighed by the cost of adverse consequences; </li></ul>
  49. 50. Potential problems <ul><li>Generic names are not as easy to remember, spell or pronounce as branded names </li></ul><ul><li>Generic products usually differ in appearance (e.g. colour, shape) from the brand and from one another, causing confusion and anxiety for patients </li></ul>
  50. 51. Potential problems <ul><li>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 </li></ul>
  51. 52. Potential problems <ul><li>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 </li></ul>
  52. 53. RECOMMONDATIONS <ul><li>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 </li></ul>
  53. 54. <ul><li>The German Section of the International League against Epilepsy requested that AEDs be excluded from regulations allowing “automatic” substitution of brand products with generics </li></ul>
  54. 55. <ul><li>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.” </li></ul>
  55. 56. <ul><li>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). </li></ul>
  56. 57. <ul><li>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. </li></ul>
  57. 58. CONSIDERATIONS
  58. 59. FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE) <ul><li>CONSIDERING THAT </li></ul><ul><li>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 </li></ul>
  59. 60. FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE) <ul><li>CONSIDERING THAT </li></ul><ul><li>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 </li></ul>
  60. 61. FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE) <ul><li>CONSIDERING THAT </li></ul><ul><li>Most AEDs have a narrow therapeutic index, i.e., their therapeutic dose is often close to the dose that causes toxicity </li></ul><ul><li>several surveys in different countries, and particularly in France </li></ul>
  61. 62. FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE) <ul><li>CONSIDERING THAT </li></ul><ul><li>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) </li></ul>
  62. 63. FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE) <ul><li>CONSIDERING THAT </li></ul><ul><li>the antiepileptic drugs constitute a particular class of drugs which makes problematic their substitution when they are used in this indication </li></ul>
  63. 64. FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE) <ul><li>RECOMMENDS </li></ul><ul><li>not to substitute by generics (and even more one generic by another) in the treatment of epilepsy, especially in patients with well controlled epilepsy </li></ul>

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