original vs generic aed 25 july 2008 - khon kaen university vs generic aed 25 july 2008.pdf ·...
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Original Original vsvs Generic Generic AEDsAEDs
How to Use It Properly How to Use It Properly Associate Professor SOMSAK TIAMKAOAssociate Professor SOMSAK TIAMKAOAssociate Professor SOMSAK TIAMKAOAssociate Professor SOMSAK TIAMKAOSrinagarind Epilepsy Research GroupSrinagarind Epilepsy Research GroupSrinagarind Epilepsy Research GroupSrinagarind Epilepsy Research GroupFaculty of Medicine, Khon Kaen UniversityFaculty of Medicine, Khon Kaen UniversityFaculty of Medicine, Khon Kaen UniversityFaculty of Medicine, Khon Kaen UniversityKhon Kaen, 40002 THAILANDKhon Kaen, 40002 THAILANDKhon Kaen, 40002 THAILANDKhon Kaen, 40002 THAILANDhttp://epilepsy.kku.ac.thhttp://epilepsy.kku.ac.thhttp://epilepsy.kku.ac.thhttp://epilepsy.kku.ac.th25 July, 200825 July, 200825 July, 200825 July, 2008Annual Meeting of Thai Epilepsy SocietyAnnual Meeting of Thai Epilepsy SocietyAnnual Meeting of Thai Epilepsy SocietyAnnual Meeting of Thai Epilepsy SocietyDeclarationDeclaration
�Funding for research, academic Funding for research, academic Funding for research, academic Funding for research, academic activity, international conference activity, international conference activity, international conference activity, international conference
from Pfizer, from Pfizer, from Pfizer, from Pfizer, SanofiSanofiSanofiSanofi----aventisaventisaventisaventis, , , , Novartis, Janssen, UCB, GSK Novartis, Janssen, UCB, GSK Novartis, Janssen, UCB, GSK Novartis, Janssen, UCB, GSK
and also speakerand also speakerand also speakerand also speaker for all companiesfor all companiesfor all companiesfor all companies
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2. .� /� – .�/��.���� original/generic
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6. ���������2�%������������ generic
DefinitionsDefinitions
Generic drug: identical, or BE to a : identical, or BE to a : identical, or BE to a : identical, or BE to a brand namebrand namebrand namebrand name drug in dosage form, drug in dosage form, drug in dosage form, drug in dosage form,
safety, strength, route of safety, strength, route of safety, strength, route of safety, strength, route of administration, quality, administration, quality, administration, quality, administration, quality,
performance characteristics and performance characteristics and performance characteristics and performance characteristics and intended use.intended use.intended use.intended use.
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Generic DrugGeneric Drug
� Process Process Process Process does not requiredoes not requiredoes not requiredoes not require the drug sponsor the drug sponsor the drug sponsor the drug sponsor to repeat costly animal and clinical research to repeat costly animal and clinical research to repeat costly animal and clinical research to repeat costly animal and clinical research on ingredients or dosage forms already on ingredients or dosage forms already on ingredients or dosage forms already on ingredients or dosage forms already approved for safety and effectiveness.approved for safety and effectiveness.approved for safety and effectiveness.approved for safety and effectiveness.� Therefore, generic medications are priced Therefore, generic medications are priced Therefore, generic medications are priced Therefore, generic medications are priced lower than brand name medications.lower than brand name medications.lower than brand name medications.lower than brand name medications.
http://www.fda.gov/cder/ogd/
Reasons Underlying Use of Generic MedicinesReasons Underlying Use of Generic Medicines
� Need by payers,Need by payers,Need by payers,Need by payers, including government, and including government, and including government, and including government, and formularies to reduce healthcare costsformularies to reduce healthcare costsformularies to reduce healthcare costsformularies to reduce healthcare costs– Congressional Budget Office estimates generics Congressional Budget Office estimates generics Congressional Budget Office estimates generics Congressional Budget Office estimates generics save consumers $8 to $10 billion a year at retail save consumers $8 to $10 billion a year at retail save consumers $8 to $10 billion a year at retail save consumers $8 to $10 billion a year at retail pharmacies (http://pharmacies (http://pharmacies (http://pharmacies (http://www.fda.gov/cder/ogdwww.fda.gov/cder/ogdwww.fda.gov/cder/ogdwww.fda.gov/cder/ogd/)/)/)/)
Limited Resources Limited Resources
AAAA ttitudettitudettitudettitudeB B B B udgetudgetudgetudgetC C C C ostostostostD D D D rugrugrugrugE E E E ducationducationducationducationF F F F acilityacilityacilityacility
AttitudeAttitude 1����+&�,�1����+&�,� 500 500 #�#�
49.8
20.0
12.0
54.2
41.8
46.6
77.4
86.0
43.0
56.6
3.6
2.6
2.0
2.8
1.6
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AntiAnti--epileptic Drugs Availableepileptic Drugs Available
52.6
16.3
0
0.3
100
94.7
20.0
8.2
100
97.9
80.0
67.4
100
97.9
100
97.6
100
97.9
100
98.7
Regional (%)
General (%)
District (%)
Community (%)
New
AEDs
VPACBZPHTPB
Education Education 1����+&�,�1����+&�,�:: 500 500 #�#�
11.8
9.6
2.4
1.6
8.0
3.6
59
48
12
8
40
18
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204
136
98
323
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Compliance with Treatment of Adult Epileptics Compliance with Treatment of Adult Epileptics
in a Rural District of Thailand. in a Rural District of Thailand.
J Med Assoc Thai 2003;86:46J Med Assoc Thai 2003;86:46--51. 51.
�Patient-compliance (100%) over 1-year was 56.9%
�Misunderstanding of need long-term treatment 48.4%
�Forgetfulness 16.1%
�Economic problem 12.8%
�Misbelieve 6.5%
�No caregiver to escort them to hospital 6.5%
����� 80808080
Facility Facility 1.1.1.1. ������� EEG EEG EEG EEG2.2.2.2. ������� MRI MRI MRI MRI3.3.3.3. �������������� �4.4.4.4. Neurologist 20 Neurologist 20 Neurologist 20 Neurologist 20 ��
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1�����%.��������1�����%.��������1. #��''�����, #��'>��/�����, "!.A����� "<�2. �!%��� >�!3. �������%���<�, �<��>���"E�4. #��%#��� �<������� -�� �<�� "��#'5. ���.�%� /�����6. #��������������,�7. ���#�%#!'������
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1. Monotherapy
2. Low initial dose3. Individualized4.4. Brand Brand namename**5. Assessment*American Association of Neurology*American Association of Neurology*American Association of Neurology*American Association of Neurology
National Guidelines for Generic PrescriptionNational Guidelines for Generic Prescription
England and Wales
� Inadequate evidence for general recommendation
Germany, Italy
� Never switch patients who are well controlled
Poland
� Pharmacist should not substitute brand without the
consent of physician
Scotland
� Formulation of AED are not interchange
Netherland
� Slow release formulation should not be
substituted
USA
� Both patient and physician should be noticed
and give consent before switching
National Guidelines for Generic PrescriptionNational Guidelines for Generic Prescription THAILANDTHAILAND
�Policy ?Policy ?Policy ?Policy ?�Clinical practice guideline ?Clinical practice guideline ?Clinical practice guideline ?Clinical practice guideline ?�Real clinical practice ?Real clinical practice ?Real clinical practice ?Real clinical practice ?�PhysicianPhysicianPhysicianPhysician’s right ?s right ?s right ?s right ?�PatientPatientPatientPatient’s right ?s right ?s right ?s right ?�SocialSocialSocialSocial’s right ? s right ? s right ? s right ?
Facts Facts
� Epilepsy is common and chronic disorder 0.5-1%
� AEDs are not generally considered expensive
� Uncertainly and unpredictability course
� Psychosocial consequences of seizures
� Wide variations in each person’s response to treatment
� UK
•53% of AEDs are generic
•20% of total drug cost
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.�/<.����.�/<.���� genericgeneric
1.1.1.1. ��#� =�2.2.2.2. '.�//!����#�3.3.3.3. ' =�������/����=��>���� ���#��'��� �
.�/��.����.�/��.���� genericgeneric1.1.1.1. ���#�%#!'#!�A�� ��"��G�A��2.2.2.2. #��'�� �E���.����3.3.3.3. �����/����%%��,��4.4.4.4. ��� .� &���'�����5.5.5.5. .�/#��''����� (�#��)6.6.6.6. �=�%%"<, �<������7.7.7.7. '<>����<�>�8.8.8.8. "�%"�/������=��� "<9.9.9.9. .�/�����N�����>'
Generic Generic Generic Generic AEDsAEDsAEDsAEDs appearance,QCappearance,QCappearance,QCappearance,QC
Generic phenytoin 16 brandGeneric phenytoin 16 brandGeneric phenytoin 16 brandGeneric phenytoin 16 brand Generic carbamazepine18 brandGeneric carbamazepine18 brandGeneric carbamazepine18 brandGeneric carbamazepine18 brand
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Bioequivalence of Generic AEDs Bioequivalence of Generic AEDs
� Essential similar to original drug
� Evaluated only in 24-36 healthy volunteers
� No data in elderly, child, drug interaction
� No study in therapeutic equivalence
� No BE in multiple drug used
� US FDA accept-20 to 25% BE compared to original
� Narrow therapeutic index
Pharmacokinetic characteristics of AEDs that may present Pharmacokinetic characteristics of AEDs that may present
problems during generic substitutionproblems during generic substitution
YesYesNo Valproate
NoYesYesCarbamazepine
YesYesYesPhenytoin
Nonlinear pharmacoki
netics
Narrow therapeutic
range
Low water solubility
Factors increasing likelihood of problems with generic substitution
AED
Seizure 2006;15:165Seizure 2006;15:165Seizure 2006;15:165Seizure 2006;15:165----76. 76. 76. 76. Issues for Generics Specific to EpilepsyIssues for Generics Specific to Epilepsy
� Characteristics of AEDsCharacteristics of AEDsCharacteristics of AEDsCharacteristics of AEDs– NonNonNonNon----linearity: slight increase in PHT bioavailability can lead to linearity: slight increase in PHT bioavailability can lead to linearity: slight increase in PHT bioavailability can lead to linearity: slight increase in PHT bioavailability can lead to marked increase in serum level and adverse effects, marked increase in serum level and adverse effects, marked increase in serum level and adverse effects, marked increase in serum level and adverse effects, especially when level is over 15 mg/Lespecially when level is over 15 mg/Lespecially when level is over 15 mg/Lespecially when level is over 15 mg/L
Crawford et al. Seizure 2006;15:168-176
864200
10
20
30
40
50
60
Daily Dose (mg/kg)
Ph
en
yto
in C
on
cen
tra
tio
n (
mg
/L)
.� /�.����.� /�.���� originaloriginal
1. #!�A�� ��"��G�A��2. ������!�1��� �����3. �����N��������� #��'�=4. "� "��'���+&�,������5. #��''�����6. �=�%%1���A��O"'��� "'�7. >���>��� route8. ��/�����
.�/��.����.�/��.���� originaloriginal
1. ��#����2. ��� .� &���'���� &�3. #��'"'��� "'����� ( �������<)4. .�//!����#�5. ������/"=� "�1�������� ���#��'��� �
Concerning Issue on Generic AEDs Concerning Issue on Generic AEDs
� Clinical course of epilepsy and nature are vary
� AEDs; adverse events, narrow therapeutic index,
variation in response
� Complexity of management regimens
– Slow titrate, drug interaction
� Bioequivalence vs therapeutic equivalence
� Economic value
� Legal situation and informed consent
Seizures 2006;15:165-76.
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Patient and physician reactions to generic AEDs Patient and physician reactions to generic AEDs
Epilepsy and Behavior 2005;7:98Epilepsy and Behavior 2005;7:98--105105
� 974 patients
� 435 physicians
� 88% of patient not accept generic AEDs
� 66% of physician not change from original to generic
� 74% breakthrough seizures
Complications arising from a switch to a generic AEDComplications arising from a switch to a generic AEDComplications arising from a switch to a generic AEDComplications arising from a switch to a generic AEDEpilepsy & Behavior 2004;5:995-8.
Brief Communication/Epilepsy
Complications attributable to a switch from a:
68
32
56
44
33
68
27
73
0
10
20
30
40
50
60
70
80
Percentage of
Responders
Break through
Seizures (n=289)
Increased Side
Effect (n=291)
Break through
Seizures (n=286)
Increased Side
Effect (n=282)
YES NO
Brand-name to generic AED? Generic AED to another generic AED?
The substitution result in any of the following (Indicate all tThe substitution result in any of the following (Indicate all that apply)hat apply)
188
168
45.9 46
23
77
2514
39
26
0
20
40
60
80
100
120
140
160
180
200
Number of
Responders
Fig. 3. Consequences of generic AED substitution
Phone consultation
Office visit
Emergency room visit
Hospital admission
Patient Injury
Missed work
Undermine relationship
I'm not sure
Not Application
OtherEpilepsy & Behavior 2004;5:995Epilepsy & Behavior 2004;5:995Epilepsy & Behavior 2004;5:995Epilepsy & Behavior 2004;5:995----8. 8. 8. 8. 20.6%
20.9%
21.3%
30%
25%
20%
15%
10%
0%
5%
20.5%
27.1%
19.5%
12.9% 11.7
%
13.4%
1.5% 1.5%
2.9% 2.7% 1.9% 1.9% 1.9%
Depakene Frisium Lamictal Statin SSRI#1 SSRI#2
All Patients
Mono-therapy
Poly-therapy
Switchback rates: Kaplan-Meier estimations. SSRI, selective serotonin reuptake inhibitor
Epilepsia 2007;48:464-9.
1.5%
2.9%
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3. '�/'<1���1=��#� /<��4. ��� ��/�!%��� >�!������� &��<���5. ���<������,�'< therapeutic window �#%6. 1�������,�'/.&@���%��/�%��������
7. 7. 7. 7. ����������#��I ���'.��/��8. Drug interaction8. Drug interaction8. Drug interaction8. Drug interaction9. Side effect 9. Side effect 9. Side effect 9. Side effect "=�10.10.10.10.�����%"�������%!##����������11.11.11.11.1�����%'<'�����#�������12.12.12.12.��� ���'��%>�&���>'�!�#��@��<����.������/.��-�#�'���.������/.��-�#�'���
EPILEPSYEPILEPSYEPILEPSYEPILEPSY
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Generic AEDs are CostGeneric AEDs are Cost--effective?? effective??
�Low cost per tablet
�Increase cost of admission
�Increase cost of TDM
�Increase cost of ER
�Psychosocial consequence
•Loss working
•Loss of driver license
���<+&�,�1=�� �<��������'<�����������<+&�,�1=�� �<��������'<��������
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Regulatory Regulatory
Process for Process for
Generics in Generics in
U.S.U.S.
http://www.fda.gov/cder/ogd/
Regulatory Regulatory
Process for Process for
Generics in Generics in
THAILANDTHAILAND
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