Generic Substitution in Patients Whose Illness Has a Narrow Therapeutic Index, Such as Epilepsy
1Department of Medicine, Conjoint Professor, South Western Clinical School, University of New South Wales, Sydney, Australia
2Professor, Medical School, Griffith University, Australia
3Professor, Chair, Medical Law, Sechenov, Moscow First State University, Russia
Received Date:January 21, 2021; Published Date: February 25, 2021
Introduction: Generic substitution is championed, claiming health economic benefits, based upon lower costs and therapeutic bioequivalences. This ignores the potential that a change in the salt or excipient may effectively change the availability of the active ingredient. This has relevance when treating conditions with a narrow therapeutic index, as seen in the management of patients with epilepsy (PWE).
What is meant by generic equivalence: This paper specifically addresses generic medications as those compounds produced by other than the innovative research based pharmaceutical company and recognises that these need to satisfy bioequivalence parameters of being within 80-125% of the parent compound at the 90% confidence level. Different generic compounds are not tested against each other but only against the parent medication.
Narrow therapeutic index: Some conditions have a narrow therapeutic index, comparing the 50% efficacy (E50) and lethal doses (L50) and considered narrow if ≤ 2. The European Medicines Association reduced acceptable bioequivalence to 90-111% (12) for treatment with a narrow therapeutic index. It is acknowledged that each formulation may have altered absorption characteristics and solubility properties, leading to possible differences in efficacy and safety. Bioequivalence studies do not account for batch-to-batch potential variations nor possible drug interactions.
Relevance to the treatment of epilepsy: Antiseizure medications (ASM) only achieve of the order of 2/3 seizure freedom, indicative of suboptimal management and need for finesse requiring stability once seizure control is achieved. This can be affected by generic substitution, recognizing that the generic medication may not be identical and respect the narrow therapeutic index. There may be many generic formulations and problems may arise when substituting one generic compound for another, especially if one is at 80% and the other is at 125% bioequivalence, thereby effectively either doubling or halving the effective dosage. While prescribing physicians, in Australia, have the option of refusing the right to substitute brands, by ticking the appropriate box on the prescription, this is not always adhered to by the dispensing pharmacist.
Specific examples in epilepsy management: Noting elevated lamotrigine blood levels in PWE who were taking the innovator, parent compound, Lamictal®, with some necessitating intervention due to toxicity, it was discovered that the pharmaceutical company had changed manufacturers thereby marketing an generic as the parent compound, claiming Good Manufacturing Practices, confirming the suspicion that the excipient caused the elevated levels. A patient, admitted to hospital for an unrelated condition, was given a generic equivalent of Keppra®, resulting in halving the blood level thereof and facilitating breakthrough seizure.
Conclusions: Generic substitution, advocated on the basis of health economic benefits, may not realize same due to inherent risks when treating PWE. There is the risk of either toxicity or breakthrough seizures with foreseeable risk of harm and resultant potential litigation. Prescribing, using proprietary trade names, may obviate risk of substitution, even of one generic for another, if indicating that brand substitution is denied, although not all pharmacists respect this directive.