generic versus brand antiepileptic drugs keppra

Generic Substitution for Brand Name Antiepileptic Drugs

Prof Dr Hussein Abdeldayem. MD

Chief of Pediatric Neurology Unit

Faculty Medicine, Alex University

Practical points

Stop attacks with no S/EStop attacks with no S/E Start with minimal dose Start with minimal dose duration : 2years from last attackduration : 2years from last attack withdraw slowly for 6 monthswithdraw slowly for 6 months DON’T CHANGE COOKERDON’T CHANGE COOKER

TreatmentTreatment

Practical Implications

CBZ, Oxcarbazepine LMT Phenytoin Gabapentin

May not work or may even exacerbate myoclonic seizures

Practical Implications –cont.

CBZ, oxcarbazepine Phenytoin Gabapentin

May not work or may even exacerbate absence seizures

GENERALIZED FITS

PARTIAL FITS

Focal with 2ry generalization FITS

Absence – Myoclonic - IS

KEPPRA

GENERALIZED FITS PARTIAL FITS

20 – 60 mg/kg/d Twice Forms:

Oral: (100mg/1ml)

250 mg tablets

500 mg tablets

Blood Follow up: NONE Onset of action Add on, no drug interaction

* Not before 4 years age

Keppra (Levetiracetam)

FDA approval for Keppra in infants and children from one month of age with partial onset seizures

January 26, 2012

Keppra® indications 

In the U.S, European Union

1- adjunctive therapy in the treatment of partial onset seizures in adults and children one month of age and older with epilepsy, myoclonic seizures

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

Generic Substitution for Brand NameAntiepileptic Drugs

Prof Dr Hussein Abdeldayem, MD

In response to increasing cost pressures, healthcare systems are encouragingthe use of generic medicines.

The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years.

Benefits

Reduction of treatment costs

assessed the risk/benefit ratio of generic substitution.

Generic Drug

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)

Generic drugSame

same qualitative and quantitative composition in terms of active substances,

same pharmaceutical form, Same strength, same route of administration, and Equivalent bioavailability (bioequivalence).

Generic drugNot like

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.

BIOEQUIVALENT

If the generic and brand name products have :

1- the same form

2- contain the same dose of the same active ingredient(s), and

3- have similar pharmacokinetic profiles,.

ARE GENERIC AND BRAND NAME AEDS EQUIVALENT?

Control group

Method:

- Single doses

- 12 – 18 serum samples/dose

Results:- TIME/CONCENTRATION

Characteristics of epilepsy

Epilepsy is a chronic disorder that requires chronic (?) AED treatment.

Avoidance of seizures is the primary goal, while keeping adverse effects to a minimum. When long-term remission has been

achieved, it becomes important to avoid even a single breakthrough seizure

1- Characteristics of epilepsy

seriousness of therapy failure

social level

personal level

self health/life

2- Characteristics of antiepileptic drugs

narrow therapeutic index,:

“ there is less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration

potential for adverse events, individual variation in response

3- Complexity of management regimens

Establishing seizure control can be difficult, need for slow titration, drug interactions

4- Potential problems

bioequivalence may not correspond to therapeutic equivalence for AEDs

Rate and extent of absorption (bioavailability) may differ between generics and branded products

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

4- PLUS

Excipients cannot be considered inactive or inert molecules

5-Evaluation of bioequivalence Individual variation

Epileptic patients vz non epileptic patients

Polytherapy AEDs Age differences

the American Academy of Neurologynoted that the ratio of generic to branded

bioavailability in individual subjects reported to

the FDA varied from 74% to 142%.

6- Continuity of supply

Switchability (FDA) Insurance service / pharmacists

7- Economic value

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.

8- Legal situation

The question arises of legal responsibility if a breakthrough seizure occurs

CLINICAL EXPERIENCE

Experience with generic substitution of

VPA

Keppra

Special categories proposed for exemption from mandatory generic substitution

Critical patients Very young, very old, those suffering from multiple diseases, those treating with poly therapy,

Special categories proposed for exemption from mandatory generic substitution

Critical diseases

Critical drugs

Epilepsy

AED

products with restrictions on generic substitution

USA-FDA : carbamazepine, phenytoin and

valproate, LVT . Spain : CBZ , gabapentin Denmark: Oxycarbamazepine Finland: All AEDs South Africa: DPH, CBZ UK: brand name prescribing for AEDs is

recommended. Sweden : CBZ, VPA, gabapentin

Seizure (2006) 15, 165—176

FDA to Tighten Standards for Generic Antiepileptic Drugs

Patients receiving levetiracetam or lamotrigine, had the highest switchback rate from generic to brand-name products

American Epilepsy Society (AES) 65th Annual Meeting Dec 2011

Conclusion

Patients with epilepsy may have a higher risk of seizures if they switch from their brand-name medication to generic anti-epileptic drugs (AEDs). 

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

References

Seizure (2006) 15, 165—176: Are there potential problems with generic substitution of antiepileptic drugs? A review of issues

Can. J. Neurol. Sci. 2000; 27: 37-43 . Generic Substitution for Brand Name Antiepileptic Drugs: A Survey

Epilepsia, 47(Suppl. 5):16–20, 2006. Recommendations of the Italian League Against Epilepsy Working Group on Generic Products of Antiepileptic Drugs

Omayma 0233051307

USE OF GENERICS IN EPILEPTIC PATIENTS

Widespread recognition exists that certain medications are not interchangeable.

USE OF GENERICS IN EPILEPTIC PATIENTS

Pharmakokinetic Consideration low water solubility (PHT & CBZ); non-linear pharmacokinetics (PHT and

valproate [VPA]); narrow therapeutic range (PHT, CBZ &

VPA).

USE OF GENERICS IN EPILEPTIC PATIENTS

AEDs are used to treat a potential serious condition

Usage duration S E Normal Life Parents stress

USE OF GENERICS IN EPILEPTIC PATIENTS

Theoretically, if patients are switched from one formulation to another, they could experience swings in plasma concentration of almost 50% Usage duration

.

USE OF GENERICS IN EPILEPTIC PATIENTS

LVT does not have a narrow therapeutic range, the relationship of plasma concentration to their clinical effects has not yet been fully

USE OF GENERICS IN EPILEPTIC PATIENTS

changes in drug blood levels may occur if a patient is switched from one company’s preparation to another

USE OF GENERICS IN EPILEPTIC PATIENTS

Several published reports have noted an increase in toxicity/deterioration upon switching to a different formulation of an AED

Tyrer JH, Eadie MJ, Sutherland JM, Hooper WD. Outbreak of anticonvulsant intoxication in an Australian city. Br Med J 1970

Potentialproblems with generic substitution included:

Potential problems

potentially serious consequences of failure of therapy, particularly in well-controlled patients

Potential problems

potential for adverse events and variability of response to AEDs

Potential problems

need for careful titration and dosing of AEDs and susceptibility of some patients to develop problems, even with small changes in drug levels

Potential problems

potential for problems from poor continuity of supply

cost savings may be outweighed by the cost of adverse consequences;

Potential problems

Generic names are not as easy to remember, spell or pronounce as branded names

Generic products usually differ in appearance (e.g. colour, shape) from the brand and from one another, causing confusion and anxiety for patients

Potential problems

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

Potential problems

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

RECOMMONDATIONS

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

The German Section of the International League against Epilepsy requested that AEDs be excluded from regulations allowing “automatic” substitution of brand products with generics

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.”

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).

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.

CONSIDERATIONS

FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)

CONSIDERING THAT 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

FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)

CONSIDERING THAT 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

FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)

CONSIDERING THAT Most AEDs have a narrow therapeutic index,

i.e., their therapeutic dose is often close to the dose that causes toxicity

several surveys in different countries, and particularly in France

FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)

CONSIDERING THAT 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)

FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)

CONSIDERING THAT the antiepileptic drugs constitute a particular

class of drugs which makes problematic their substitution when they are used in this indication

FRENCH CHAPTER OF THE INTERNATIONAL LEAGUE AGAINST EPILEPSY (LFCE)

RECOMMENDS not to substitute by generics (and even more

one generic by another) in the treatment of epilepsy, especially in patients with well controlled epilepsy