In a retrospective review of 760 epileptic patients, a significant proportion of patients taking generic levetiracetam needed a switch back to the original brand-name drug because of an increase in seizure frequency and adverse events, including blurred vision, headache, depression, memory loss, aggression, and mood swings.52 Similarly, substitution to generic phenytoin was associated with decreased seizure control compared with the branded version. Switching from branded to generic phenytoin also resulted in 22%–31% lower plasma drug levels with generic drug compared with the brand-name drug.54
A questionnaire conducted by the FDA among 196 neurologists reported decreased clinical efficacy and increased seizure frequency and adverse events among their patients after generic substitution of antiepileptic drugs. Approximately two-thirds reported increased seizure frequency and 56% reported increased adverse events.57
In another survey, cases of loss of seizure control followed by generic substitution were reviewed among physicians.37 In total, 50 patients who were well controlled on a branded antiepileptic drug experienced a breakthrough seizure or had an increase in seizure frequency after generic switching. Almost half of the patients on the generic drug had lower drug serum levels at the time of the breakthrough seizure. Clearly, the studies referred to above underscore a clear theme of citing safety, toxicity, or efficacy concerns where brand-to-generic switching is concerned in the area of antiepileptic medications. However, as noted below, outcomes for this particular condition can also translate into cost-based concerns that are not favorable to brand-to-generic switching.
In a further survey of 1354 epileptic patients, high switch-back rates from generics to brand-name antiepileptic drugs (12.9%–20%) were reported compared with antihypertensive agents and antidepressants (1.5%–2.9%).51 Again, this was because of increased toxicity and/or loss of seizure control associated with the use of generic antiepileptic drugs.
In contrast to antiepileptic drugs, antipsychotics, antidepressants, and benzodiazepines are generally believed to have a somewhat broader therapeutic window, and dosing is adjusted based on clinical efficacy or rate-limiting adverse events. Desmarais et al33 conducted a thorough literature search to evaluate the effectiveness, tolerability, adherence, and economics of generic psychotropic medications. Table 2 lists different adverse consequences and adherence issues reported in patients administered generic psychotropic drugs. Relative to the widespread use of generics in these psychotropic medication classes, only a few case reports exist on clinical inequalities, such as switch-related increases in adverse events or re-emergence of symptoms. For example, re-emerging or worsening symptoms were observed in 20 patients after a brand-to-generic switching of citalopram. Emerging symptoms included suicidal ideation, increase in anxiety, obsessive thoughts, compulsions, irritability, and depressive thoughts. Although the previous treatment response was restored after switching back to the innovator brand-name drug, the time required for restoration was greater than the time taken for the re-emergence (0.7–12 weeks vs. 0.58 weeks, respectively).56
Each of the above highlights the complexities involved when evaluating the economic benefits of switching to generics. Total cost of care and, in some cases, potential indirect costs are among the more comprehensive measures of the true cost of switching to generics. Indeed, each case, condition, or therapeutic entity may represent a unique circumstance requiring careful study before considering its true impact.
Although in many cases generics may represent an appropriate alternative, mandatory generic switching may lead to unintended consequences. The present review highlights that generic substitution may lead to concerns among patients, which can lead to challenges in drug adherence. The studies reviewed highlight the existence of negative attitudes toward generic products in a sizeable minority (∼33%) of the patients. Some patients believed that lower prices translated into poorer quality, whereas others believe that economic savings were the reason that they had accepted the generic product. Changes in physical attributes of their medicine added to their uncertainty. Some patients reported a different effect or new or more adverse events. In the case of chronic illnesses, patients who were familiar with their drugs by appearance were less prepared to accept the switch.
Many patients who were surveyed believed that general physicians and pharmacists should discuss generic substitution more actively with them and wished to receive further information, as this would impact their decision to accept the substitution. Furthermore, the research implied that patients would generally prefer the medications to be prescribed by their physician.
Clearly, there are differences in the success rates, either measured by switch-back rates or overall costs of care, prevalence of side effects, toxicity, and/or efficacy based on the therapeutic class of agents undergoing the switch. This is particularly relevant to agents that have narrower therapeutic indices compared with other classes of drugs. For example, in the treatment of epilepsy, significant issues have been documented after generic switching, including breakthrough seizures, more adverse events, and increased cost of care because of extra physician visits or hospitalizations.
Given these observations, the significance of considering the overall impact of generic substitution on medication adherence should be carefully considered for each indication and circumstance relative to their presumed economic benefit. Adherence to treatment should be focused on several levels, including the patient, the health care provider, and the health care scheme. Patients require the knowledge, attitudes, and skills to adhere to an appropriately prescribed treatment regimen. Similarly, health care providers are required to follow established treatment guidelines, make certain that patients are aware and understand the reason for their prescribed medications (branded or generic), any potential adverse effects, interactions with other drugs, and how their medicine should be taken, as well as make certain that the suggested treatment regimen is the simplest possible. If the health care system insurer or the patient cannot afford the branded medication, then the justification and support for generic switching should be explained to the patient, so as not to adversely affect adherence. With a thoughtful approach, the true cost of the medications and consequences of generic switching may be more appropriately considered.
To the best of our ability, we have attempted to include examples of what has been published on the impact of generic substitution. Although we did note a publication bias toward the reporting of negative findings, we do believe that our review is of value as it heightens awareness of the issues surrounding generic substitution.
In summary, caution and careful consideration should be given when implementing a generic switching policy. Based on our review, in certain therapeutic areas, physicians and patients should retain the right to request the branded product when medically justifiable. Generic switching should be assessed on an individual basis, and with disclosure of possible consequences to the patient and a plan to implement the change and assess its ultimate impact through education and monitoring.53
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