Switching Antiepileptic Drugs: Benefits Versus Risks

Changing antiepileptic drugs might improve seizure control and/or reduce adverse effects, but the risks of a switch must be considered.

Patients switch medications all the time. When many drugs fell off the “patent cliff” in 2012 and 2013, switching from a brand name drug to a generic was rampant. (Forty brand name drugs that had generated more than $35 billion in annual sales lost their patents in 2012, and about half that many were affected in 2013.¹) Most patients hop from one antihypertensive to another or use the least expensive generic antibiotic with no problems. Patients who have epilepsy may need or want to switch antiepileptic drugs (AEDs) for a number of reasons (Table 1). Switching to a different AED can frighten epilepsy patients and their caregivers and affect seizure control. Breakthrough seizures can be life threatening.²

For decades, regulators and clinicians have had concerns about AED switching, especially with older drugs. The most enduring concern has been brand-to-generic switching. Initially, the concern was that bioequivalence test procedures were insufficient to identify differences between brand and generic AEDs; the concern extended to other drugs with narrow therapeutic indexes. Now the concern has evolved to acknowledge that generic-to-generic switching may also produce clinically important differences that may result in seizures.⁴ For example, if a patient switches from a generic that is 5% less bioavailable than the brand to a generic that is 5% more bioavailable than the brand—the extremes allowable by the FDA—the drugs will differ in bioavailability by 10%.² (How much of a difference does 10% make? It depends on the patient. Those who have mild epilepsy or are well controlled may not notice the change. Those who are fragile or barely controlled may.)

The traditional answer to this problem (marking prescriptions with “brand name only”) ensures that the patient receives the same product consistently. But patients may do well if they receive the same generic consistently. Requiring a brand name prevents patients from receiving adequate care at a reduced cost when generics can be used.

Where’s the Proof?

Three similarly structured retrospective studies used case-control analyses to determine the probability of having an epilepsy-related event requiring acute care among patients who recently switched AED formulations. All studies included brand-to-generic, generic-to-brand, or generic-to-generic switches and compared study subjects with patients who did not switch. They monitored ambulance use, emergency department (ED) admission, or hospitalization. The studies found a significant increase in events among the patients who switched (n = 2164) compared with patients who did not (n = 6492), even after adjusting for baseline differences in the cohorts. The odds ranged from 1.57 to 1.84.^5-7

In another study, a team of researchers followed patients taking phenytoin or carbamazepine as monotherapy for focal epilepsy who were switched to a different AED; patients were monitored for 6 months. The researchers matched each of 43 patients in the “switching” arm to 2 controls of the same seizure status who remained on anticonvulsant monotherapy. The researchers found:

• Most patients who were seizure free (ie, those who switched due to side effects or possible long-term consequences) remained so after switching to a new AED (just one-sixth had seizures). However, patients who were seizure free before the switch were 6.5 times more likely to experience seizure recurrence than seizure-free patients in the control group, who did not switch medications.
• Patients who initially were not seizure free, however, had the same odds of being seizure free if they remained on the same drug as they did if they switched.
• Seizure remission was more likely (but not significantly so) when patients remained on the same drug.
• Regardless of their pre-switch seizure status, patients who switched from older AEDs to newer agents with different mechanisms of action were no more likely to be seizure free.

Based on their findings, the authors concluded that most improvements in drug-resistant patients who have focal epilepsy are probably spontaneous remissions rather than responses to new AEDs.⁸

Other studies, including one that involved 1490 patients taking AEDS (745 in the switching and nonswitching arms), have found that patients who switched from brand to generic phenytoin, divalproex, or lamotrigine did not experience a greater incidence of all-cause ED visits or hospitalizations.⁹ Further, some studies have found that the behavior of switching by itself and even refilling the same brand AED may lead to seizure-related events regardless of the medication or type of switch.^10,11

The Real Concern: The Patient

Seizure control is crucial to patients who have epilepsy. Many health care clinicians think of seizure as just the event—the seizure—and the potential for patient injury. They forget about the later and socially devastating consequences. Afterward, patients may lose their driving privileges or employment or suffer from anxiety, depression, or low self-esteem. Clinicians also need to remember that if the sole impact of switching is increased adverse events, the impact can be as burdensome as having a seizure. Adverse events can lead to hospitalization, discomfort, and work or school absences.^2,12

Patients who have epilepsy need the most cost-effective drug that works. They also need reassurance when they are switching AEDs, and pharmacists need to help them and their families monitor closely.¹² Online Table 2 lists dispensing and monitoring safeguards.

Table 2: Tips for Safe Dispensing of Antiepileptic Drugs

• Know your state law; several states require a pharmacist to contact the prescriber and the patient before substituting a brand name AED for its generic.
• NDC codes are specific to formulation; track NDC numbers associated with patients’ specific AEDs.
• Educate your pharmacy buyer to consistently stock the same generic AEDs—not the cheapest at the time of ordering.
• When periodic contract changes occur or patients fill prescriptions at different pharmacies, stress to patients the importance of knowing their specific AEDs.
• Remember that when an enzyme-inducing AED is started, enzyme induction is a gradual process. When an enzyme-inducing AED is discontinued, de-induction will be related to the half-life of the inducer and the enzyme degradation rates. Monitor patients’ other medications that are metabolized by CYP enzymes.
• Realize that patients are often fearful of switching AEDs, but they also have concerns about costs. Remind patients that they will adhere to their medication better (and be less likely to have seizures) if it’s affordable. Reinforce that the differences between a brand AED and a generic AED are usually small, but using the same generic consistently is wise.

AED = antiepileptic drug; NDC = national drug code.

Adapted from references 2-4, 13, and 14.

End Note

Controversy about switching AEDs continues. The American Epilepsy Society and the American Academy of Neurology recommend against switching from brand to generic AEDs without prescriber and patient permission.¹³ The most prudent approach is to be sure that patients and their health care teams weigh the risks and benefits of switching, and remain suitably vigilant during the switch. Although changing AEDs can be emotionally difficult for patients, it is also an opportunity to improve seizure control and/or reduce adverse effects.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy with interests in medical history and how society views and addresses issues related to prescription drugs.

References

• Thomas K. Generic drug makers see a drought ahead. New York Times. December 3, 2012. www.nytimes.com/2012/12/04/business/generic-drug-makers-facing-squeeze-on-revenue.html?pagewanted=all&_r=0. Accessed January 4, 2013.
• Garnett WR. Switching AED formulations: defining the issues. Adv Stud Pharm. 2008;5:140-145.
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• Zachry WM, Doan QD, Caldwell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia. 2009;50:493-500.
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• Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013;54:11-27.
• Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology. 2007;68:249-250.
• Thomas RH, Mullins JM, Hammond CL, Smith PE, Kerr MP. The importance of the experiences of initial diagnosis and treatment failure when switching antiepileptic drugs. Epilepsy Behav. 2013;29:492-496.