Requirements for generic antiepileptic medicines: a clinical perspective

Abstract

Many antiepileptic drugs (AEDs) are now available as a generic product. This can potentially save the healthcare providers massive costs. Hence, governmental authorities have introduced rules and incentives for clinicians to switch from the original branded AED to a generic product. Clinicians and patients with epilepsy are reluctant to switch. The licensing of generic AEDs is based on the equation that bioavailability means therapeutic equivalence. However, from a clinical standpoint one has to consider several other relevant issues: (1) Do generic AEDs have the same efficacy, safety and quality? (2) Can generic AEDs be used as substitutions for brand AEDs? (3) Can generic products of AEDs be used interchangeably? (4) Does the generic AED manufacturer guarantee the long-term consistency of availability on the market? (4) Do generic AEDs reduce the costs, and--if so--are these costs worth any additional risk to patient's safety? This article reviews the clinical issues related to current bioequivalence, prescribability, and switchability of AEDs.

Adjusted Indirect Treatment Comparison of the Bioavailability of WHO-Prequalified First-Line Generic Antituberculosis Medicines

“…However, these arguments fail to consider that 80–125% is the acceptance range for a ratio between the pharmacokinetic parameters, AUC and C max of test/reference, and therefore 0.8 and 1.25 represent a ±20% difference because the comparison between test and reference is carried out as a ratio, and the inverse of 0.8 is 1.25. Other authors 17 prefer to claim that a patient who is treated with a generic that exhibits a 20% lower BA and is subsequently switched to a generic with a 20% higher BA is exposed to a 56% increase in dose because 125 is 156% of 80, again ignoring that 125% represents only a 20% increase in BA because test and reference are compared by means of ratios. It is important to highlight that such an event is extremely unlikely (<1%).…”

Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update

“…Though all generic AEDs are bioequivalent with the original (brand) product, there may be large differences in plasma concentrations between two generic products, if the bioavailability of the two products is at the boundaries of the acceptance interval [45]. Moreover, the design of the studies used to investigate bioequivalence (mainly single-dose studies in healthy volunteers under highly standardized conditions), do not guarantee that the products concerned will also be bioequivalent in an individual patient during chronic use [46]. The situation is even more complicated for compounds with non-linear kinetics (such as phenytoin), or when there is no clear correlation between plasma concentration and therapeutic effect.…”

“…When choosing between the brand or one of the generic versions of an AED the likelihood of continuous supply of the compound from the same manufacturer should be taken into account [15, 46]. Prescription of an AED based solely on the active substance by International Non-proprietary Name (INN), without any indication of the brand or manufacturer, should be avoided.…”

Interchangeability among carbamazepine formulations: the impact over epilepsy patients

“…In clinical practice, a matter of concern relates to the interchangeability among the different formulations of commercially available antiepileptic drugs. Studies suggest that switching among formulations may increase the risks of seizures occurrence and intoxication, what might affect the patients' quality of life (Guilhoto et al, 2009;Trinka, Kramer, Graf, 2011). Perucca et al (2006) do not recommend switching from a reference to a generic drug in case of those patients who achieved seizure remission, as well as Virgínia P. Frade, Maria J. N. Paiva, Isarita Martins, Whocely V. Castro, Vinícius S. Belo, André O. Baldoni, Priscila .F.…”