Switching to Generic Antiepileptic Drugs (AEDs) Mitra Habibi, PharmD Clinical Pharmacist, Clinical Assistant Professor College of Pharmacy University of Illinois at Chicago

Antiepileptic Drugs (AEDs) The first AED, Phenobarbital was discovered in 1912 Since then >20 more AEDs have been approved The brand name – the name given to the new drug by the manufacturer The generic name – the chemical name for that specific drug

Brand Drugs Once a drug is discovered, the manufacturer gets patent protection from the Food and Drug Administration (FDA) for about 20 years Usually takes about 6-7 years for a drug to reach the market Studies to check how the drug works in the body making sure the drug is safe and effective in treating seizures The remaining 13-14 years, no generic company can make the drug Currently, all AEDs approved before 2005 are available in generic form

Antiepileptic Drugs Felbamate 1993 Phenobarbital 1912 Gabapentin 1994 Phenytoin 1938 Primidone 1954 Ethosuximdie 1960 Carbamazepine 1974 Clonazepam 1975 Valproic acid 1978 Felbamate 1993 Gabapentin 1994 Lamotrigine 1994 Topiramate 1996 Oxcarbazepine 1999 Levetiracetam 1999 Zonisamide 2000 Pregabalin 2005 Lacosamide 2008 Rufinamide 2008 Vigabatrin 2009 Ezogabine 2010 Clobazam 2011 Perampanel 2012 Eslicarbazepine 2013 Brivaracetam 2016

Brand Drugs Once the patent protection for a brand drug expires Other companies can apply to get permission from the FDA to make/sell the generic form of the drug These companies do not need to repeat all the initial animal and human/patient studies that the original company had to complete to show safety/efficacy of the drug Significantly decreasing the cost of making generic medications As a result, generic drugs are sold at a lower price compared to brand, decreasing overall cost

Brand drugs In order to get FDA approval to bring generic form of the drug to the market, the generic drug company must show that their generic form: Has the same active material as the brand drug The inactive material can be different (color/taste/form) Be identical in strength to have the same amount of drug, for example: 100mg tablets Have the same dosage form (tablets, capsules, etc.) The same administration (be taken by mouth or given by injections)

Generic Drugs In addition: The generic drug should: Have the same use (example: partial seizures) Be manufactured under the same standards Tested in a group of healthy volunteers to show no significant difference in Maximum blood level between the brand and generic forms of the drug Total amount of drug absorbed by the body

Generic Drugs Concerns about switching brand/generic AEDs Not enough drug absorbed, possible loss of seizure control Too much drug absorbed, experiencing side effects

Generic AEDs Researches have checked to see if there are significant differences Reviewed > 83,000 patients taking generic AEDs Reviewed type of generic form filled at previous month Compared to generic form filled ~ 3 months earlier Reviewed if both AEDs were from the same generic company or not Looked for increased risk of having seizures Found out no additional risk for seizures with generic drugs even if AEDs were switched to different generic company Kesselheim et al., Neurology 2016;87:1798-1801

Generic AEDs Other examples: Researches have compared lamictal (lamotrigine) Differences in brand lamictal versus generic lamotrigine Differences between two different generic forms of lamotrigine Patients in many different centers across U.S. were tested Patients had similar blood levels, similar total drug absorption overall difference of <3% which was not significant Ting et al., Epilepsia 2015;56:1415-1424 Privitera et al., Lanct Neurol 2016;15:365-372.

Generic AEDs Other researchers have also looked at differences in AED blood levels in individual patients for Topiramate (Topamax), levetiracetam (Keppra), Lamotrigine (Lamictal) Noticed day-to-day differences in blood levels even if patient had remained on the same brand product Concluded that these differences in blood levels may not be related to brand-generic substitution Contin M, et al., Epilepsy Research 122:79-83

Generic AEDs Important to note that: Some AEDs more sensitive to dose changes and subsequent blood levels Phenytoin – complex metabolism (small changes in dose results in significant changes in blood level) Carbamazepine – variable absorption with different formulations There is also the issue of patient “outliers”

Generic drugs Pharmacies can change generic suppliers depending on cost and/or which generic drug is available Brand medications are substituted for generic forms as a cost- saving measure Insurance companies in general will not approve brand version if generic form available If offered, the co-pay cost may be substantially higher for patients This practice will continue

Generic AEDs Some issues: May cause concerns in patients (am I going to have more seizures?, am I going to have side effects?) If switched between different generic companies, may cause confusion Looking different (shape, size, color) However, the investigations in switching brand to generic AEDs shown to be safe Resulting in similar medication absorption and blood levels

Generic AEDs Tell your physician if you notice any difference Ideal situation To remain on the same product/generic company Tell your physician if you notice any difference Most concerns can be addressed by monitoring patients closely and adjusting the dose based on: changes in blood levels, changes in seizure frequency