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1 .. E-mail: [email protected] http://epilepsy.kku.ac.th August 11, 2008 How to Use Antiepileptic Drugs in 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 Epilepsy in Thailand USA....... Limited resources

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Page 1: Get involved Get inspired - Khon Kaen University

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E-mail: [email protected]://epilepsy.kku.ac.th

August 11, 2008

How to Use Antiepileptic Drugsin Limited Resources ���������� ����������

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�� ��� ��...�"#�� �����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

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Epilepsy in Thailand

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Page 2: Get involved Get inspired - Khon Kaen University

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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

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56.6

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�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

Page 3: Get involved Get inspired - Khon Kaen University

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Education &�����'�(�: 500 ��

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Multidisciplinary Approach

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Page 4: Get involved Get inspired - Khon Kaen University

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Srinagarind Epilepsy Research Group

� Epileptologist

� Internal medicine, psychiatrist

� Pediatric neurologist

�General practice

� Pharmacist

�Nurse

� Pharmaceutical industry

�Company: AIA

September 9, 2003���������

��� ���

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Page 5: Get involved Get inspired - Khon Kaen University

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���������<+,���H�

�CBC, BUN, Cr, electrolyte, Ca, Mg, PO4, LFT

���<+�*:.��[���.��

�98% ����

EEG � 40% of epileptics were normal

� 10% of normal persons were abnormal

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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

Page 6: Get involved Get inspired - Khon Kaen University

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

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Page 7: Get involved Get inspired - Khon Kaen University

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�������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

Page 8: Get involved Get inspired - Khon Kaen University

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

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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

Page 9: Get involved Get inspired - Khon Kaen University

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)

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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 10: Get involved Get inspired - Khon Kaen University

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%

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Page 11: Get involved Get inspired - Khon Kaen University

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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

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Page 12: Get involved Get inspired - Khon Kaen University

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Page 13: Get involved Get inspired - Khon Kaen University

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Nurse Prescribing and the Management of Epilepsy

��>��D'%'�jD!cc���,�-k.1!-�$(F���,-.'-,� GP

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Page 14: Get involved Get inspired - Khon Kaen University

14

Status epilepticus: pitfall management

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E-mail: [email protected]://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

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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

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