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Tighter Standards Ahead for Generic Epilepsy Drugs?

Tighter Standards Ahead for Generic Epilepsy Drugs?

thera_subStudies are underway that may lead the FDA to stiffen its bioequivalence rules for generic anti-epileptic drugs (AEDs) and others with so-called narrow therapeutic indices, researchers said here.

These studies — which, unlike those required from generic manufacturers under current FDA regulations, examine drug pharmacokinetics in epilepsy patients and under chronic dosing — could show that some current generic AEDs vary enough to put patients at risk.

The FDA has shown a willingness to modify its rules if, indeed, the evidence is there, said Barry Gidal, PharmD, of the University of Wisconsin, at a press briefing held at the American Epilepsy Society (AES) annual meeting. “We’re bringing the evidence.”

Michael Privitera, MD, of the University of Cincinnati and the AES’s vice president, who is leading some of the new studies, said that, when the organization and others first suggested to the FDA that modifications for AEDs and other narrow-index drugs were needed, the agency resisted.

But after seeing preliminary evidence from open-label studies and analyses of generic manufacturers’ bioequivalence data, FDA officials have now “agreed that perhaps there should be some studies.”

And, in fact, it has provided funding to conduct them. Privitera said that results should be forthcoming next year, although he cautioned that the FDA tends to move slowly.

Current bioequivelance regulations allow some variation in generic drug pharmacokinetics relative to the original branded drug. In particular, the lower boundary for 90% confidence intervals in measures of bioavailability can be as low as 80% of the mean for the branded drug, and the upper boundary can be as high as 125% of the branded drug mean.

Small studies have found that, when generic versions of the same drug but from different manufacturers are compared with each other, they can vary more than when compared with the branded drug. Therefore, when a pharmacy changes suppliers, the variations can put patients at risk either for breakthrough seizures because of inadequate blood levels, or toxic effects from excessive drug exposure.

Privitera pointed out that, under current FDA rules, single-dose studies in healthy volunteers are adequate to show bioequivalence. He said that this poses two problems: drug availability and metabolism may be different in patients than in healthy people, and it may also be different with chronic dosing.

Consequently, the FDA is funding two studies addressing those problems, Privitera said. Both involve lamotrigine (Lamictal): one will examine single-dose pharmacokinetics of two different generic versions in 54 patients with epilepsy, and the other will test two generic versions in 36 patients when dosed daily for approximately 2 weeks.

Lamotrigine was a reasonable choice, Gregory Krauss, MD, of Johns Hopkins University in Baltimore, told MedPage Today, because it has been the source of many physician and patient complaints about generic equivalence.

But Krauss said he didn’t expect the studies to find a great deal of variation. Other drugs such as oxcarbazepine (Trileptal) have shown more variability in maximal concentrations and total exposure in earlier studies, he said.

On the other hand, a benchtop study of lamotrigine dissolution presented at the AES meeting Monday indicated a reason for concern. Conducted by a team that included Gidal and Privitera, it found that the amounts of dissolution after 15 and 30 minutes of generic tablets made by six different companies varied from each other substantially, and also among different dosage strengths (25 versus 100 mg).

There was considerable variability even among different lots from the same manufacturer, the study found, and the results did not always match those submitted by the manufacturers to the FDA in their marketing applications.

The issue of real-world generic equivalence is not confined to AEDs, Privitera said. Immunosuppressants are another drug class with narrow therapeutic indices, and an FDA-funded study of tacrolimus bioequivalence is also underway.

Another view of the bioequivalence issue was provided by another University of Cincinnati study led by Lisa Garrity, PharmD — a survey of Cincinnati-area pharmacists about their knowledge and experience with generic AEDs.

Garrity and colleagues obtained responses to a one-page questionnaire from 30 retail pharmacists who had a mean of 15.6 years in practice (SD 8.8). Of these, 20 reported having no specific education about possible issues with generic AEDs when switching from one manufacturer to another.

Responses indicated that 22 believed that switching from a branded version to a generic could cause problems, but only 18 said that issues could arise when switching between generic versions of the same drug. “I think these [types of switches] should be equally concerning,” Garrity said.

Most of the respondents (26) said they verbally inform patients when a drug supplier is changed, but the same number said they did not inform the patients’ physicians. Nearly as many, 24, said they made efforts not to change AED manufacturers.

But, when asked about the FDA’s current bioequivalence standard, most of the pharmacists got it wrong. Three said the generic versions had to exactly match the branded drug’s pharmacokinetics, and 16 put the acceptable variability at 90%-111%. Only 11 correctly indicated the actual standard of 80%-125%.

Privitera said that the FDA has said it would consider a new standard of 90%-111% for certain narrow-index drugs if new studies support it.

Gidal said another problem with the current system is the lack of transparency regarding generic drugs’ pharmacokinetics. Data from manufacturers’ FDA submissions “are not readily available,” he said. “It should be available on a web site.”

But he also cautioned against fomenting worry about generic drugs, which he and Privitera agreed are good for most patients and a necessary component of cost-effective care.

It’s important to raise questions and urge the FDA toward improved standards to protect patients, but “we need not make patients fearful,” Gidal said.

The bioequivalence studies are funded by the FDA. The pharmacist survey had no external funding.

Presenters had no financial disclosures.

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23 Comments

  1. It’s about freaking time!

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  2. It’s about freaking time!

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  3. I take the generic all the time. I am just hoping that there will be a good investigation in this. For years I have paid so much. They need more studies in this field

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  4. Finally… Lots of breakthrough seizures on generic!

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  5. Finally!!!! Thank goodness!!!

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  6. As I now have to pay a higher premium on my drugs so i dont have to be on the generics its about time we make it so the generics have to be similar to the originals!

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  7. I take the generic of depakote cant afford the real deal stuff

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  8. It’s about time!! Great!!

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  9. My daughter takes the generic of Depakote too! Makes me nervous

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  10. Somebody certainly needs to tighten up on generics. For a person with epilepsy they cannot afford to have the drug on a roller coaster ride in the persons blood. They need to have same amount with each pill and dosage. Generics only deliver between 65-75% of the drug in each dose. That’s pathetic!! Therefore seizures keep happening and the drug written off as not working for the patient when it actually might have had they received the guaranteed dosage amount that a name brand does. People forced to use generic because name brands are very expensive. I will make necessary sacrifices to make sure my daughter has name brand over generic due to this lack of consistency with generics. People need to research more and educate themselves instead of always relying on a doctor or pharmacist to say generics are as good as name brands. They are NOT, not by a long shot!!

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  11. This is awesome news. Taylor had a bad reaction to the generic lamictal. The general public for the most part have no idea about all the fillers that a put into generics. I certainly did not, mostly because there is so much emphasis on the fact that they both share the same “active ingredients”

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  12. It’s good they have generic but bad thing is I can’t take them because my body will not absorb them even the Dr. Was like this is crazy so I only can take premium brands of topamax, vimpat, quite a few more but being insured ya u can afford them but no insurance topamax by itself is like $5000-$7000 bucks that’s insane vimpat about about 2000 or more and now the beginning of the year it’s going to be more that’s just exajuration!!!

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  13. well its about time i had i dont kno at the seizures due to the fact of bad meds i think wat neurologist called it.

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  14. My daughter has always taken generic meds. They don’t make me nervous one bit. However, what makes me nervous is when they switch manufacturers. That is what you need to be careful of. We watch her prescriptions bottles carefully. We are aware of the drug manufacturer for her seizure meds and if we see anything odd we take her meds back to the pharmacy. Sometimes, however, parents can get too comfortable and that is when accidents happen. It’s usually when our children go seizure free for a period of time that our guard gets let down. I was told by a doctor before that if someone’s seizures are not controlled well, then he will have them take brand name, but if they are pretty easy to control with medication then generic is fine. That is the rule of thumb that I use. Some people need the brand name meds. Some of us can tolerate generics. I have been on seizure meds my whole life and have taken generics just fine. However, we need more awareness about Epilepsy. The medications alone are so expensive that some people can’t take their medications or are forced to try others because they can’t afford them. This is very sad.

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  15. yes generic dose not work for epilepsy

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  16. how can we help to push this?

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  17. Generic is just as it says a cheap imitation of the real stuff I have to have my levels checked cause it stops working

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  18. The compounds are a problem depending on the chemical makeup- they are either lacking in some compounds making up the anti-epileptic meds with cutting the dose. I have had this with my meds and had to alter them to work. It was like pulling teeth to have the Doctors to understand ,, hey care to look into this. It is my life ya know.

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  19. The compounds are a problem depending on the chemical makeup- they are either lacking in some compounds making up the anti-epileptic meds with cutting the dose. I have had this with my meds and had to alter them to work. It was like pulling teeth to have the Doctors to understand ,, hey care to look into this. It is my life ya know.

    Reply
  20. Great News! Hope the pharmacy companies and insurance listen!

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  21. Michelle, I am not against generic drugs. But it is staying on the same pill daily, not constant switching that matters for me.

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  22. I have been on Tegretol since 1995. My neurologist says there is a difference in the name brand and the generic, so he always marks on my prescription “name brand only.”

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  23. It ticks me off when we know the generic isn’t strong enough for my son and have to pay extra $$$ for name brand. If there is a study to prove this, count us in! Drug companies and insurance don’t seem to think this is true but how would they feel having to watch their kid have a seizure?

    Reply

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