View
4
Download
0
Category
Preview:
Citation preview
1
��.��.������ �������������������������� �������������������� �������� �!������"����� �
E-mail: somtia@kku.ac.thhttp://epilepsy.kku.ac.th
August 11, 2008
How to Use Antiepileptic Drugsin Limited Resources ���������� ����������
1.����������������������
2.�������������������
�� ��� ��...�"#�� �����Get involved Get inspired
World Health Organization
�5% of the population have a single seizure
�Prevalence: 8.2 per 1,000 population
�More than 10 per 1,000 in developing countries
�50 million people in the world have epilepsy
�Incidence: 50-100 per 100,000 population
Key Message from WHO
�70% of epilepsy responds to treatment
�But in developing countries 25% of people received the treatment
10 cases every 1 minute
50 million
80% in developing countries
Only 40% were treated
$����%������������� 2 ������������������������������ 1��� ����� ������������� 2-5 � $�%�����&���'���� �(�)��*���'+���� �&��.$� �/��0�12&��'���� � ���� %��$�%���%/ �/��0�12&��%/���$0��&3�
Epilepsy in Thailand
����� �( �(�)����� ����4� USA.......
����� �( ���������9�*���;�
� �����������
�<���1��=� � ������ �<>��������
� �?@��� ��0���������
������+ ��;0
Limited resources
2
Limited Resources A ttitudeB udgetC ostD rugE ducationF acility
Attitude &�����'�(� 500 ��
49.8
20.0
12.0
54.2
41.8
46.6
77.4
86.0
43.0
56.6
3.6
2.6
2.0
2.8
1.6
1. ��3�$����%���������4����4���������������5����������67�7���� ���3�����
2. 8 �����9��5�7�6� �8 ���� ���������3�$����%��:�7
3. 8 �����9��5�7�6� �8 ���������������3�$����%��:�7
4. 8 ��5�79�����8 �8 ���� �����&67�;��$����%��:�7
5. &67�;��$����%���������<���=����������:�7
:� ��3��7��
(�7����)
��3��7��
(�7����)
:� ���
(�7����)
Budget
�����������
��������� !�
�����"#$%���
Cost
���'(�)*+��
���'�,-.'+��
���'�/0$1'�+��
Drug ��'�'(�3'$��������1!-4����'�'
��'5$ CPG �����5$4����'�'
�Generic vs Original
Anti-epileptic Drugs Available
Type of hospital PB PHT CBZ VPA NewAEDs
Regional (%) 100 100 100 100 52.6
General (%) 97.9 97.9 97.9 94.7 16.3
District (%) 100 100 80 20 0
Community (%) 98.7 97.6 67.4 8.2 0.3
3
Education &�����'�(�: 500 ��
11.8
9.6
2.4
1.6
8.0
3.6
59
48
12
8
40
18
�����#<���6
���"C�(� ���"��
�6�"�D�����8�:������
��������8D���$8(
:� "������
�#��E
�7����FG��������� �$����%������F����:� (���:�7����� � 1 7�)
&�����'�(�
40.8
27.2
19.6
6.4
0.6
4.2
204
136
98
32
3
21
������8��������%����
������8�����4"���������%���8 ���<�
������8���������� 2 – 5 �H
������8���� 3 – 6 ��#��
������8�����4"��5��7��� '<� 15 ��G���#� ���"��/���$��
�#��E
�7����FG�������������8����
&�����'�(�
79.6
47.2
45.2
38.9
31.0
27.9
398
236
226
192
155
137
��D�5�7����% �����#�&67�;�� ��%�� (���:�7����� � 1 7�)
5%7%7����#� �� �� 7�� 35 5�����"#���J������������<� �7��������%������� � 5 ��8� ��#� �������%��K<G� 5�7�G� $�"�����
������������
�����#<�&7�8������� ����
��87�&67�;��
�J�����������F3�8������ ��%��
�7����FG����
Facility �-'�(�)* EEG
�-'�(�)* MRI
�-'�(�)*�>/,��'-,$?,-
�Neurologist 20 �$
�L9��&67�;��$����%��1. ���$��2. �L9����������3. �L9�����(M��F4. �L9�������67����� 7�5F5. �L9��8��$������6. �L9��8��8G���7. �L9��8�����:� � 7�5F8. �L9���������8�, ����9. �L9�� ����������5F10.�L9��8�����:� �'���������
Multidisciplinary Approach
�������=��=��.$�=���������
�������=�������
���� 3����� ��
�������=�� 360 ����
�'+������+�����
4
Srinagarind Epilepsy Research Group
� Epileptologist
� Internal medicine, psychiatrist
� Pediatric neurologist
�General practice
� Pharmacist
�Nurse
� Pharmaceutical industry
�Company: AIA
September 9, 2003���������
��� ���
�����������������
�������������������/�� (21 min)1/3 �&67�;��8�� �������'�(� :�7����������F4��&��
-'�)0$0*C,� �4�-'DE0/�/F 1/3 : 3 F
�Fit
�Faint
�Funny turns
-'�)0$0*C,�: +$)1'�
����(��)*�������� �+�,-+.�� ���
����/� VDO clip
�6��� �����.7��89��
�,� VDO ��������,�:�., +<��=
-�+�:.��>���*:.���� CT-brain
���(�>.E��+��)����:� 25 �G(���5?�1!-�'�)
�����9�(��)��,������.� ���� *��
��������9� ��� ���H):H,����,����>I����*�.
�+���������E�.-/>�, ���E��������H�
-�+�:.��>���*:.���� MRI-brain
���������, CPS ���H):�+�*�+.�:+�����O�
������������,�����O������.=
��� refer ������� ��������������
5
���������<+,���H�
�CBC, BUN, Cr, electrolyte, Ca, Mg, PO4, LFT
���<+�*:.��[���.��
�98% ����
EEG � 40% of epileptics were normal
� 10% of normal persons were abnormal
���������� ����5�7�����%��
����������%��5�7���#��7�����<8����
�&����F�����7��8����
����=�"%������8����
7����"�F�����$������%��K<G�
�&����F�����%��
�&����F��������(�
Risk from AEDs1. Bone disorder 2. Body weight 3. Metabolic acidosis 4. Renal stone5. Thyroid disorders 6. Lipid disorders 7. Reproductive system
Risk of Rx
Risk of seizureVs.
Start AEDs NO
6
Risk of RxRisk of seizure
Vs.
Start AEDs YES
Firstmonotherapy
Alternativemonotherapy
Polytherapy
Pharmacoresistance
Seizure-freedom
Seizure-freedom
Seizure-freedom
Epilepsy Treatment Surgery
Prognostic model for prediction of seizure recurrence for first seizures and early epilepsy
Seizure number Score One seizure at presentation 0Two seizures at presentation 1Three or more seizures at presentation 2
Add if present Neurological disorder/deficit, learning +1disability, or developmental delay
Abnormal EEG +1
Medical Research Council MESS Study Group. Lancet Neurology 2006;5:317-22.
Risk classification group Final score Low risk 0Medium risk 1High risk 2-4
Prognostic model for prediction of seizure recurrence
Medical Research Council MESS Study Group. Lancet Neurology 2006;5:317-22.
When to Start AEDs
1. > 2 unprovoked seizures 2. First seizure +
- Definitely : Structural lesion
Sibling with epilepsy
Previous focal pathology
Status at onset
- Probably Excessive sleep deprivation
�����������������%��
��������F4�� 100%
������5F� �����
��������������7�� ��4"�������
7
�������5%7�����%��1. Monotherapy2. Low initial dose3. Individualized4. Brand name*5. Assessment
*American Association of Neurology
DefinitionsDefinitions
Generic drug: identical, or BE to a : identical, or BE to a : identical, or BE to a : identical, or BE to a brand name drugbrand name drugbrand name drugbrand name drug in dosage form, in dosage form, in dosage form, 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.
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 to to to repeat costlyrepeat costlyrepeat costlyrepeat costly animal and clinical research animal and clinical research animal and clinical research 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 yearsave consumers $8 to $10 billion a yearsave consumers $8 to $10 billion a yearsave consumers $8 to $10 billion a year at retail at retail at retail at retail pharmacies (http://pharmacies (http://pharmacies (http://pharmacies (http://www.fda.gov/cder/ogdwww.fda.gov/cder/ogdwww.fda.gov/cder/ogdwww.fda.gov/cder/ogd/)/)/)/)
National Guidelines for Generic PrescriptionNational Guidelines for Generic Prescription
England and Wales
� Inadequate evidence for general recommendation
Germany, Italy
� Never switch patients who are well controlled
Poland
� Pharmacist should not substitute brand without the
consent of physician
Scotland
� Formulation of AED are not interchange
Netherland
� Slow release formulation should not be
substituted
USA
� Both patient and physician should be noticed
and give consent before switching
National Guidelines for Generic PrescriptionNational Guidelines for Generic Prescription
8
THAILANDTHAILAND
�Policy ?Policy ?Policy ?Policy ?�Clinical practice guideline ?Clinical practice guideline ?Clinical practice guideline ?Clinical practice guideline ?�Real clinical practice ?Real clinical practice ?Real clinical practice ?Real clinical practice ?�PhysicianPhysicianPhysicianPhysician’s right ?s right ?s right ?s right ?�PatientPatientPatientPatient’s right ?s right ?s right ?s right ?�SocialSocialSocialSocial’s right ? s right ? s right ? s right ?
1���1����1���1���� genericgeneric
1.1.1.1. ����_+�2.2.2.2. (�1����������3.3.3.3. (�_+����;������+�)$)�����0�����3���
1����1����1����1���� genericgeneric1.1.1.1. �����������9<�� ���>0 @0<��2.2.2.2. ����;��%/��1����3.3.3.3. ���;0�;�����0� 4.4.4.4. ����1�_2���(�=�5.5.5.5. 1�������/)� (��;0)6.6.6.6. �+�=��>�, ����/�=���7.7.7.7. ��$�����/$�8.8.8.8. >�>(����)�+���� >�9.9.9.9. 1������?���)$�
Generic phenytoin 16 brandGeneric phenytoin 16 brandGeneric phenytoin 16 brandGeneric phenytoin 16 brand
Generic carbamazepine18 brandGeneric carbamazepine18 brandGeneric carbamazepine18 brandGeneric carbamazepine18 brand
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
9
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----linearitylinearitylinearitylinearity: slight increase in PHT bioavailability can lead to : slight increase in PHT bioavailability can lead to : slight increase in PHT bioavailability can lead to : 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)
1���1����1���1���� originaloriginal
1. ��9<�� ���>0 @0<��2. ����� �'�0; �0��3. ����?��0����� �����+4. >��>�0�����2����0��5. �����/)�6. �+�=��'�0;<9c>�/3��>��7. $���$��� route8. ;0�;����
1����1����1����1���� originaloriginal
1. ����=��2. ����1�_2���(� /�_2�3. ����>�/3��>��;/3� (�*�����9�)4. 1����������5. ���;���>+� >�'����)�����0�����3���
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.
10
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%
1��3���1���������1��3���1���������1. �������;��;��%/�� $������ 2-3 �2. ����������=;����&�>�'���� ��������
- 1�������/)�- ���1��_ 3���
3. �0(���'�;�'+���������4. �����0����;0�$;��;���_2����0;5. �� �/)������� therapeutic window =��6. '��������(�(�12&�����������
7. 7. 7. 7. ���)���;�����e ��0/�1����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.'���� ����������3�����12.12.12.12.;����0/��$2/�)$� ����&� �/��1��3���1���������1��3���1���������
11
�����������S��������������S��� genericgeneric
1. ��������������T����U�2. �������V�S��3. ���������WX��Y!�Z�U�4. ���������[��S[!�Z�U�
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
=� �����)������=� �����)������
'+���)$�
– ����� original / generic original / generic original / generic original / generic �f(�_�������(�– ���1�� ;����������� _������������(�(�– _�(������;����������� )� usual dose usual dose usual dose usual dose ��– _��� generic generic generic generic ���;��)�1���� �/>+���� usual usual usual usual dose dose dose dose ��9���(���'�= ��g������
=� �����)������=� �����)������'+������
– (��������/�>���0�1������� original original original original (��� generic generic generic generic _������������(�
– (��������/���/$�1������� genericgenericgenericgeneric–_�(� generic generic generic generic =�������������(�(� �����0/�1����>+���� usual doseusual doseusual doseusual dose
1�����h0�;0��9�)���1�����h0�;0��9�)��� generic generic AEDsAEDs1.1.1.1. ����������1���i��������2.2.2.2. ���=��)$=� �=��'+��� ������>��3.3.3.3. ��������;0�;��=���j�������;�i����
'�0;�� generic generic generic generic ����;��%/��4.4.4.4. (��������/���0� '+�3�$���� (��/$�)5.5.5.5. _���0/�)������ new casenew casenew casenew case6.6.6.6. ������������� breakthrough seizures breakthrough seizures breakthrough seizures breakthrough seizures&67�� ��� ��� �"8��, ������%�%�", ��M���� "������ �=�%��� ����%�������� ���(�8���%�� 9���&67�;��� �����6� ���F7�, �����7���� �#��E
12
�8��8 ��"8�������F4��
�5�7������(�
�5�7�G�����G�8��������
�5�7�G���5F�����������5F
�8��8 �"������5�7��������5F �G���5F�5�7�G�����G� ���8����'�(��5�7������(��M�"�������#<��7��������6�����(��������
�8��8 ��=�%�������G� �������������5%7��� �&67�;������"8��
�5�7�G���'�(���#����� �&67�;������"8��
-'��,-.'1�a�/FE �D�F'��)'��bF�)'��cF'5*1�adb-(F���e')0%�-'��,-.'1�a��'� ���f,�fF�$�e')0%�-'��,-.'1�a�� compliance Db�D!/���'5?F*�'��!F���'1�aD!/��)'�D,��,$%g�>e)�'�+�1�g EbF"h)�(F��/�
�i'�b/1�a+�1�g�b/����
�����"#$������(F��(-5*����(F��1i'�>��
�� &67�;�����9���:� %��
Physician Pharmacist Nurse
7 7 7
Easy Epilepsy Clinic
13
Nurse Prescribing and the Management of Epilepsy
��>��D'%'�jD!cc���,�-k.1!-�$(F���,-.'-,� GP
�+�1�g GP ���D'�'�d�,-.'EbF"h)��/F *l�(F��D��(��
�+�1�g�C�'>1'���*i'$)$����������c'/+� $
�Epilepsy Nurse Specialist (ENS) service
Epilepsia 2006;47:669-71
������������ ���� ���������������
���������� ����� �
������FG����&67�;��$����%��������FG����&67�;��$����%��
������$����%��������$����%��$�"�������������8��$�"�������������8��
����"8����������"8������ �����8����� ���� ������8����� ���� �
%#��-���&67�;��.....................................����...........�H8����6 ...........................................................................................................................................................$8���"8�(�7��)...............................�#��#�...................����4���4������ �.....................................................HN.............................. Epilepsy No............................�8D�8�������(�.....................................................������������%����#��.....................................................%��� ����%��(5�7�����8 x ��7� 7�8������������8����[� �����8:�7����� � 1 7�( )�.���%��8��8G���:�$��:� �67��� 8G�K<G�E( ) .���%��8�������(���7�� ���3 ������8�<�����[�"��E( )�.���%��8������� ���� �����<�( ).���%��8������67��������:� :�7���������E( )F.�#��E ���������.................................................�����......................................................................�������7�...........................................................................
���������� ����� ���������
�8��8 ���M�����G�����$����
��������
��������
�8��8 �������%�%�"�����$����%��
���������8��8��
���%��8������ �E
� �7���������678�����������8������ % ����7: �L9�� gap of treatment
���� ��$���� ���������� ���������[�F��
14
Status epilepticus: pitfall management
��.��.������ �������������������������� �������������������� �������� �!������"����� �
E-mail: somtia@kku.ac.thhttp://epilepsy.kku.ac.th
August 11, 2008
Physiologic definition
�Epileptic activity without complete normalization of neuro-chemical and physiological homeostasis
Clinical definition�Recurrent seizures without full and complete recovery of consciousness
�Single prolonged convulsion lasting
over 30 minutes
�Continuous, generalized, convulsive seizure
lasting more than 5 min.
�Unreasonable to wait 30 min before initiating AED
�Refractory SE is seizures lasting more than 1 hr.
Practical definition
Treatment : Aim�Stop epileptic activity as rapidly as possible
�Protect neurons from seizure-induced damage
�Preventing recurrences managing precipitating
factors and treating complication
General treatment of GTC SE1. Cardio-respiratory function 2. Emergency investigations 3. Initial emergency treatment 4. Intensive care and seizure/EEG monitoring 5. Prevent and treatment complication 6. Establish etiology
15
Early VS delay treatment �SE treated 30 min after onset was terminated in 80%
�SE treated 120 min after onset was terminated in 40%
�Treatment SE should be initiated ASAP
�Out-of-hospital treatment
Thai CPG
Pre-monitoring stageDiazepam 10 mg iv (given over 2-5 min) or rectally,
repeated once 15 minutes later if status continues to threaten
Or Lorazepam 4 mg iv bolus
If seizures continue or status develops
Stage of established statusPhenobarbital iv infusion of 10 mg/kg at a rate of 100 mg/min
(i.e. about 700 mg in an average adult over 20 min)Or
Phenytoin iv infusion of 15 mg/kg at a rate of 50 mg/min(i.e. about 100 mg in an average adult over 10 min)
If status continues after 30-60 min
Sodium valproate IV form
25 mg/kg loading dose
Alternative drug in Thai Epilepsy CPG
Stage of refractory statusGeneral anaesthesia with either:
Propofol 2mg/kg iv bolus, repeated if necessary, and then followed by continuous infusion of 5-10 mg/kg/h initially
Or
Thiopental: 100-250mg iv bolus given over 20s, with further 50mg boluses every 2-3 min until seizures are controlled
Thiopental should be slowly withdrawn 12 h after the last seizure
High mortality and morbidity
Failure to emergency treatment
1. Inadequate drug treatment− too low dosage − too slow rate IV infusion − no maintenance AEDs
2. Additional medical factors − complication − causes
3. Misdiagnosis
_�� �)�����`��: E����.E��H-
������������)����:� 5 ���� ���*.*�:�� ��[� SE
���������O���)E����.�����O�
��cd�� �.+:�.������,�:+��<�+.
�� �._�� subtle GTC
Recommended