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1 Original Original vs vs Generic Generic AEDs AEDs How to Use It Properly How to Use It Properly Declaration Declaration 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, Sanofi Sanofi Sanofi Sanofi-aventis aventis aventis aventis, , , , Novartis, Janssen, UCB, GSK Novartis, Janssen, UCB, GSK Novartis, Janssen, UCB, GSK Novartis, Janssen, UCB, GSK and also speaker and also speaker and also speaker and also speaker for all companies for all companies for all companies for all companies : 1. 360 2. original/generic 3. 4. 5. original/generic 6. generic Definitions Definitions Generic drug : identical, or BE to a : identical, or BE to a : identical, or BE to a : identical, or BE to a brand name brand name brand name brand 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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Page 1: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

1

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

������������������

��������������� ������� �����������������������������

��

��� !��"�#��� !��"�# :: ���% &����% &�

1. ���'�� 360 ��+� ��������,�-�#�'���

2. .� /� – .�/��.���� original/generic

3. 1�����%.��������

4. .������/.��-�#�'���

5. #��'#!'#�.��������� original/generic

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.

Page 2: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

2

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

1. /;�-�#�'���'<#��' ��<�����/���#��'"�'�� ����� �<���=������ /;����

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Page 3: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

3

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

��� �E@�>'=

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136

98

323

21

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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 ��

Page 4: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

4

360360 ��+���+�......������,�-�#�'���������,�-�#�'���

1. 1�������,� : #�%#!'������, #!�A���<���

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1�����%.��������1�����%.��������1. #��''�����, #��'>��/�����, "!.A����� "<�2. �!%��� >�!3. �������%���<�, �<��>���"E�4. #��%#��� �<������� -�� �<�� "��#'5. ���.�%� /�����6. #��������������,�7. ���#�%#!'������

Page 5: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

5

>����������������>����������������

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

Page 6: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

6

.�/<.����.�/<.���� 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

Page 7: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

7

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.

Page 8: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

8

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%

Page 9: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

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=�� �<��������'<��������

Page 10: original vs generic aed 25 july 2008 - Khon Kaen University vs generic aed 25 july 2008.pdf · Inadequate evidence for general recommendation Germany, Italy Never switch patients

10

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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.�#��2�%������<����.�#��2�%������<���� generic generic AEDsAEDs1.1.1.1. #�� ��-�%��.����Q������/ ��2.2.2.2. #������>�������1=�����%��� "'�3.3.3.3. #��'<�����/��'��� R������'���Q�����

1����� generic generic generic generic ������ �E���4.4.4.4. '#�� �<���%��,��1=���>����� (�<�>�)5.5.5.5. � ���'��#�� � new casenew casenew casenew case6.6.6.6. #��'<��������� breakthrough seizures breakthrough seizures breakthrough seizures breakthrough seizures"�!"�! :: R��.�#�/R��.�#�/1.1.1.1. 1=��#�� �+=������2.2.2.2. ������������ '����%/�� 360 ��+�3.3.3.3. ��N�������� #��' >'��"'�������<4.4.4.4. '/%��������� original original original original "'� EPILEPSYEPILEPSYEPILEPSYEPILEPSY