Elite Pharmaceuticals Inc (ELTP)

[WeeZuhl]

Makes me wonder, how many of their actual generics have such a T-max issue, and if not, why the issue only with SOx?

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Hmmm, I say. Why do oxycodone tablets show the Tmax for the oral solution? When you trace the data back to the original NDA, it very clearly states: “The food effect for the to-be marketed tablets can be extrapolated from the food effect on IR solution.” The tablets and solution were bioequivalent in the fasting state, but the tablets were not tested in the fed state. If the original Roxicodone tablets were never tested for fed bioequivalence, were any of the currently-marketed generic tablets tested for BE after a high-calorie meal? Does the FDA even know the fed Tmax data for the array of available tablets?

Does it make a difference? Is the fed Tmax different for the tablet vs. solution? After all, the brand name for the solution is OxyFast- maybe it really is faster. Isn’t that why abusers chew (or also “parachute”) their oxyIR/Percs/Norco- for faster absorption and quicker high. Maybe the fed Tmax of “Roxicodone tablets” isn’t as tidy as the FDA thinks, and maybe SequestOx is being unfairly judged against oral solution. Since Nasrat has never released the data, the controls used in ELI-200 studies are unknown. We know it was a three-way crossover (that sounds hot!) but not if any control formulations were tested in the fed state. “Three-way crossover” sounds to me like #1 Roxicodone fasting, #2 SequestOx fasting, and #3 SequestOx fed. This means that SequestOx failed to be bioequivalent to FDA data and not to an oxycodone “fed control” group run in crossover with ELI-200. In other words, SequestOx did not fail head-to-head, instead it failed against what the FDA deems to be the proper fed Tmax. This is very important, especially if the FDA data on fed Tmax is as sketchy as it seems.

SUMMARY

1. Original Roxicodone tablets were never tested (or at least never reported) under high-calorie fed conditions.

2. Every oxycodone tablet sold in U.S. carries a label that reports the food effect data (Tmax) of oral solution instead of tablet. It is unknown how many, if any, of the currently-marketed generic tablets were tested for bioequivalence after high-calorie meal. Many times ANDA applications are granted “in vivo waivers,” meaning their bioequivalence is assumed based on “in vitro” biochemical analysis.

3. Currently-approved oxycodone 5mg capsules have significantly slower Tmax compared with oral solution- double the Tmax effect and well-outside of the range of bioequivalence with oral solution. These capsules are not considered to have a food effect and do not carry instructions to take on an empty stomach.

4. Currently-approved oxycodone 5mg capsules have Tmax after high-cal meal of 3 hours. Bioequivalence standards require SequestOx to be within 125%, or 3 hours 45 minutes. If SequestOx fed Tmax is equal to or less than 3 hours 45 minutes, then it is already bioequivalent to Lehigh Valley NDA #200-534 and could be immediately approved in 5mg size if RLD is changed.

5. Lehigh Valley Pharmaceticals received Approval for oxycodone 5mg capsules, despite significantly delayed fed Tmax, without any food-effect labeling or safety concerns. The commentary which may explain why this was allowed has been redacted from the NDA’s Summary Review, which is signed by FDA’s Dr. Sharon Hertz. A Freedom of Information Act Request has been submitted by me for the redacted discussion.

6. While there is a significant difference in the effect of a high calorie meal on Tmax of oxycodone solution compared with capsules, there is no published data regarding the fed Tmax of tablets. In a three-way crossover pivotal BE study, it is unlikely SequestOx had any “fed control” arm with tablets. Nasrat likely has access to tablet fed Tmax data because of Elite’s work on Epic’s oxycodone tablet ANDA. This may be the kind of information he is collecting to show FDA.

7. Avridi used oxycodone tablets as a fed control, but the data is reported as “median” instead of “mean,” so it is not comparable to published data. Extrapolation suggests the mean is slower than the reported median for both Avridi and oxycodone tablets, but it was not suggestive of major Tmax difference between oxycodone tablets and solution. Based on my guesstimation, if Avridi reported fed Tmax as “mean” instead of “median”, it would look even worse, greater than 5 hours (and therefore outside the bioequivalence range of even the Lehigh Valley capsules). Avridi has detergent ADF, but SequestOx does not.