Aim : to stop attacks No attacks / No S/E Start with minimal dose and increase gradually Stop if side effects appeared Don’t withdraw AED suddenly but gradually Do not change cooker
Keppra® was previously approved in the U.S. as adjunctive therapy for partial onset seizures in adults and children four years of age and older with epilepsy.
Formulary committees, health policy makers, consumer groups and others may see the increased use of generic products as an important tool in the battle to control healthcare costs
There are presently 26 different generic preparations for five brand name antiepileptic drugs(AEDs) on the Canadian market with others likely to be released in the near future
More available – in - More available – from-
The original producers of the drug bear the research and development costs while the companies producing generics also benefit despite the fact that they did not contribute to the development of that drug and in general, do little to promote new drug development.
Generic drugs must meet federal manufacturing standards for identity, strength, quality, purity and potency and provincial standards for clinical e q u i v a l e n c e
differences in non-medicinal ingredients and manufacturing process may result in variations between generic and brand name products in such factors as taste, shelf life, dissolution rate and extent, in vivo pharmacokinetics and appearance
Bioequivalence implies (but does not guarantee) that a drug will have the same therapeutic and adverse effects as the reference drug
Acceptance criteria in ministry of health The bioavailability of a generic drug is compared with that of the brand name drug by administering each as single doses to the same volunteers at different times. Approximately 12 to 18 serum samples are collected per subject per dose and a plot is made of serum concentration versus time. From this plot, a number of important pharmacokinetic parameters are calculated which measure the rate and extent of drug absorption and predict the mean steady-state serum concentration during chronic administration. It should be noted that these studies are almost always carried out in fasting, young, healthy, male adults, close to their ideal body weight, using single doses of the drug rather than in actual patients with epilepsy taking multiple doses and often multiple medications that may interact.
Just one seizure after a period of control can have major implications at the social level (e.g. school problem, loss of driving license, loss of employment) and at the personal level (e.g. risk of injury, loss of self-esteem, family stress ). There may even be fatal consequences–—the risk of death in patients with uncontrolled seizures is higher than in seizure-free patients There is, therefore, considerably more at stake when treating epilepsy than with many other conditions, such as peptic ulcer, when any slight loss of efficacy on changing product would be expected to have limited consequences
1- Many AEDs are considered to be treatments with a narrow therapeutic index (i.e. only a small relative difference in dose between therapeutic and toxic effects). A narrow therapeutic index implies that slight variations in drug absorption could result in significant negative health outcomes. 2- The FDA considers a drug to have a narrow therapeutic index if: there is less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration; safe and effective use requires careful titration and patient monitoring 3- Even AEDs with low toxicity and with a wide therapeutic index, such as lamotrigine, require titration to the optimal dose
If adequate control of seizures is not achieved with a tolerable dose of one or two AEDs in sequential monotherapy, then other AEDs are often added as adjunctive therapy, again with titration according to the therapeutic response. As a result, many patients with epilepsy are on a daily regimen of multiple treatments that has been carefully adjusted to obtain the optimal response.
bioequivalence, as defined by regulatory bodies, may not correspond to therapeutic equivalence for AEDs, because of the permitted range of bioavailability for generics, evaluation methods that use small numbers of relatively young healthy volunteers and individual variation;
Furthermore, despite the lack of specific regulations concerning the excipients in a generic formulation, these substances cannot be considered inactive or inert molecules, as different salts of the same active drug can have distinct chemical and biological properties
The evaluation of bioequivalence in a population of patients with epilepsy is not the same as establishing bioequivalence for healthy volunteers. It is well known that patients with epilepsy respond to AEDs in different ways, so that individual titration of doses is required. Bioequivalence studies are usually carried out with single doses on small numbers of healthy volunteers (usually young adults) who are not receiving other therapies. This is done in order to eliminate factors (such as the presence of a disease state) that may cause variations in the results. In the clinical situation, patients with epilepsy often receive multiple drugs. Many patients are likely to be older or younger than the adults used in standard tests, with consequent differences in drug handling characteristics. Some commentators have raised concerns about the accepted methods for evaluating bioequivalence
Once a number of generic products are on the market, pharmacists may change their supplier according to price and availability. A patient stabilised on one AED may be at risk of that control being lost if the prescription is changed to a formulation from a different manufacturer. In the USA, the FDA has used the term prescribability to describe the use of a generic as first therapy, and the term switchability for the use of a generic in a patient already established on therapy
Either as a starting or as changing The question arises of legal responsibility if a breakthrough seizure occurs when the medication a patient has previously received is changed for another
Critical disease: Intercurrent disorders, mainly in chronic care, where drug-disease interactions present major problems, those with serious clinical sequelae, should therapy fail Critical drugs: Narrow therapeutic index, those requiring a complex therapeutic regimen, those with considerable drug interactions, those requiring titration of individual doses
In Denmark, some AEDs containing oxcarbamazepine are exempt from generic substitution \\because of bioequivalence problems 2006 add gabapentin as new drug with old low theurapeutic indexes drugs
Recur szs or increase szs Although newer AEDs, such as lamotrigine, gabapentin, topiramate and levetriacetam, are not considered to have a narrow therapeutic range like carbamazepine or valproate, some of the issues of concern still apply. Like the older AEDs,they require individual titration, and the consequences of a breakthrough seizure are the same, regardless of the therapy that failed
Widespread recognition exists that certain medications are not interchangeable. This mandate has been applied to some commonly used drugs including digoxin and warfarin.
The following risk factors for problems with generic substitution apply to certain antiepileptic drugs: low water solubility (PHT & CBZ); non-linear pharmacokinetics (PHT and valproate [VPA]); and narrow therapeutic range (PHT, CBZ & VPA). Antiepileptic drugs, such as phenytoin (PHT) and carbamazepine (CBZ), have long been recognized as drugs which should not be substituted because of their narrow therapeutic index and pharmacologic properties.3 , 5 C a r b a m a z e p i n e , phenytoin and valproate are listed as narrow therapeutic index drugs by the FDA and there are seven states which restrict the substitution of one or more of these drugs
Apart from pharmacokinetic considerations, antiepileptic drugs are generally used to treat a potentially serious condition. Unexpected breakthrough seizures in a controlled patient could lead to adverse psychosocial consequences such as loss of job or driver’s licence, physical injury or, rarely, death. In a controlled epileptic patient who is driving, an unexpected seizure could also endanger pedestrians or other motorists
Although newer antiepileptic drugs such as lamotrigine, vigabatrin, gabapentin and topiramate are not considered to have a narrow therapeutic range, the relationship of plasma concentration to their clinical effects has not yet been fully e s t a b l i s h e d
British Epilepsy Association survey found that 46.5% of people perceived a deterioration in their condition after being switched to a different supply of the same AED.
Use of generic products may inhibit research and innovation
The original manufacturer may apply for many patents: for the chemical, different dosage forms or strengths and even the manufacturing process, and each generic manufacturer must determine if enough of the important patents have expired to make it worthwhile to market a particular drug.
Generic Substitution for Brand Name Antiepileptic Drugs Prof Dr Hussein Abdeldayem. MD Chief of Pediatric Neurology Unit Faculty Medicine, Alex University
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)
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.
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.
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
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).