Caritas Malta Epilepsy Association Epilepsies, AEDs and Health Issues: The Love-Hate Relationship Janet Mifsud Caritas Malta Epilepsy Association Epilepsy Society of Malta Vice President Europe IBE

Caritas Malta Epilepsy Association

Caritas Malta Epilepsy Association ‘If it were not for the great variability between individuals, medicine would be a science not an art.’ Sir Walter Osler 1882

Caritas Malta Epilepsy Association What do we know about epilepsy ?

Caritas Malta Epilepsy Association Facts: Epilepsy, affects as many as 6 million people in Europe, is a heterogeneous chronic disorder characterized by recurrent seizures: which differ in nature types of seizures age at onset aetiology

Caritas Malta Epilepsy Association How is it treated?

Caritas Malta Epilepsy Association Bromide Phenobarbital Phenytoin Primidone Ethosuximide Sodium Valproate Benzodiazepines Carbamazepine YEAR AEDs Vigabatrin Zonisamide Lamotrigine Felbamate Gabapentin Topiramate Fosphenytoin Oxcarbazepine Tiagabine Levetiracetam Pregabalin Eliscarbazepine

Caritas Malta Epilepsy Association Yet: No single AED is appropriate in all types of epilepsies since the causes of epilepsy are extremely diverse: genetic and developmental defects infections and trauma neoplastic degenerative disease processes

Caritas Malta Epilepsy Association Yet…. Despite the large number of AEDs that suppress or prevent seizures are now available, so far, drug therapy available will only control the onset of seizures There are no pharmacological treatments that cure epilepsy or modify the detrimental course of the disorder.

Caritas Malta Epilepsy Association Why? What do drugs do? IMBALANCES → DISEASE → CORRECTION FROM OUTSIDE ‘Bugs’ Chemicals FROM INSIDE Too little Too much Eliminate threat Prevent /treat with anti-infectives Agonist Antagonist P.K. Rangachari, IUPHAR 2010

Caritas Malta Epilepsy Association How to decide?

Caritas Malta Epilepsy Association clinical experience social implications basic mechanisms DRUG industry users dispensersprescribers regulators

Caritas Malta Epilepsy Association How to decide: What is the problem?

Caritas Malta Epilepsy Association How to decide: which drug?

Caritas Malta Epilepsy Association Explicit knowledge codified published transmissible Tacit knowledge procedures experiences values How to decide: which drug?

Caritas Malta Epilepsy Association Which drug? Other factors….. The selection of the appropriate AED also depends a variety of specific factors age underlying physiological conditions. etc The prognosis and quality of life of a person with epilepsy varies considerably. In addition, about 30% of patients, remain resistant to drug treatment. This has major implications not only for other health issues, but also for independent living, education and employment, mobility, and personal relationships.

Caritas Malta Epilepsy Association As there are no major differences in efficacy among first-line antiepileptic drugs, tolerability and long-term safety must be the paramount consideration in patients with epilepsy. Kwan P, Brodie MJ. Neurology 2003; 60 (suppl 4): S2-S12

Caritas Malta Epilepsy Association AEDs..when to start? Whether to treat first seizure is controversial 16-62% will recur within 5 years Relapse rate might be reduced by antiepileptic drug treatment Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increase relapse risk Quality of life issues are important

Caritas Malta Epilepsy Association AEDs: how to? Correct therapeutic choice only after diagnosis emphasis on monotherapy not polytherapy care in special populations e.g. children, pregnant women folic acid in females keep epilepsy diary keep same doctor many months needed to adjust dose Be aware of factors which may precipitate onset of seizures e.g. sleep deprivation, substance/ alcohol abuse, computer/TV games in children (?), stress other treatment e.g. homeopathy? regular discussions with parents/ teachers co-operations in - medication taking, correct observations

Caritas Malta Epilepsy Association Choosing an AED  Seizure type  Epilepsy Syndrome  Pharmacokinet ics  Interactions  Other medical conditions  Efficacy  Adverse effects  Cost Partial seizures phenobarbital phenytoin carbamazepine valproate gabapentin tiagaine lamotrigine topiramate levetiracetam oxcarbazepine zonisamide felbamate rufinamide eslicarbazepine Absence seizures ethosuximide valproate TonicClonic seizures  carbamazepine  phenytoin  felbamate  topiramate  tamotrigine  valproate  levetiracetam  zonisamide  oxcarbazepine

Caritas Malta Epilepsy Association Does the ideal AED exist? Effective in refractory patients Low toxicity and no significant side effects Interacts minimally with other drugs Can easily be titrated Works via a logical mechanism of action Broad spectrum –no seizure aggravation High efficacy, good tolerability No contraindications Friendly pharmacokinetics / once daily dosing Availability of a friendly pediatric formulation Availability of parenteral formulation

Caritas Malta Epilepsy Association Which AED to choose first?  Pick a drug with a spectrum of activity and side- effects/interaction profile that has the potential to produce seizure freedom without longterm consequences  Match the choice to the patient’s seizures and/or epilepsy syndrome, gender, age, weight, psychiatric and other comorbidities, risk of teratogenesis and concomitant medication etc.  COST MUST ALSO BE TAKEN INTO CONSIDERATION

Caritas Malta Epilepsy Association AEDs : AEDs : matching drugs to patients Treatment failure is also often related to side effects or inability to tolerate the AED. Several studies have shown that CNS, neuropsychological, systemic, and idiosyncratic adverse events lead to treatment failure in up to 40% of patients. For those patients who remain on AED therapy, the side effects may contribute to a decreased quality of life.

Caritas Malta Epilepsy Association Traditional AEDs For nearly 8 decades just 6 key AEDs. Phenobarbital (Luminal) Phenytoin (Dilantin) Primidone (Mysoline) Benzodiazepines Ethosuximide (Tegretol) Carbamazepine (Tegretol) Valproic acid (Depakine)-1967 Associated with severe problems PK/PD Narrow therapeutic indices  more adverse effects Extensive hepatic metabolism  more drug interactions Non linear kinetics  large interindividual variation

Caritas Malta Epilepsy Association New AEDs ‘the boring drugs’ Since 1993, several new AEDS promised improved tolerability with different safety and efficacy profiles Felbamate (Felbatol) Fosphenytoin (Cerebix) Gabapentin (Neurontin) Lamotrigine (Lamictal) Levetiracetam (Keppra) Oxcarbazepine (Trileptal) Pregabalin (Lyrica) Tiagabine (Gabitril) Topiramate (Topamax) Vigabatrin (Sabril) Zonisamide (Zonegran) Zebinex (Elsicarbezepine) new formulations and chemical alterations of traditional AEDs

Caritas Malta Epilepsy Association What did they promise? Broad spectrum of activity Fewer side effects and better tolerability Increased ease of use Linear kinetics Protein binding Lack of drug interactions Little liver metabolism and no toxic metabolites Rapid titration and less frequent dosing schedules No TDM needed

Caritas Malta Epilepsy Association Which AED? Don’t forget drug interactions

Caritas Malta Epilepsy Association Don’t’ forget drug interactions… ‘It is important for the clinician to recognize that treatment with AEDs, particularly the older enzyme inducing drugs …, may complicate the management of other co-morbid disorders. For example, cardiovascular disease and perhaps affective disorders (i.e. depression) may be commonly encountered in the patients with epilepsy of all ages, but particularly the elderly. So don’t forget: drugs used in the treatment of hypertension drugs used in the treatment of lipid disorders anticoagulants drugs used in the treatment of depression Check out Virepa course on AEDs

Caritas Malta Epilepsy Association Generic AEDs..what to do? Generic vs originator products Excipents

Caritas Malta Epilepsy Association Are AEDs forever?

Caritas Malta Epilepsy Association Why stop AEDs ? Side effects …….. Drug interactions…. The bother of having to remember to take them, to pack them, and to renew them every month. Even the idea of needing medicine and the associated stigma is philosophically distasteful to some people EXPENSE

Caritas Malta Epilepsy Association Discontinuing AEDs - when to consider it…  Seizure freedom for  2 years implies overall >60% chance of successful withdrawal in some syndromes  Favorable factors Control achieved easily on one drug at low dose No previous unsuccessful attempts at withdrawal Normal neurologic exam and EEG Primary generalized seizures except JME Consider relative risks/benefits (e.g., driving, pregnancy)

Caritas Malta Epilepsy Association Yet, if they are stopped… There is the increased risk of having a seizure. SUDEP loss of driving license. Impaired quality of life?

Caritas Malta Epilepsy Association So…get the correct info.. Advice from your national medicines authority

Caritas Malta Epilepsy Association ‘If it were not for the great variability between individuals, medicine would be a science not an art.’ Yet we can get there…