Bioequivalence and Bioavailability Forum

Hi John,

❝ […] FDA is a bit strange. They ask for EtOH in-vitro dose dumping test on drugs liable for abuse like Methylphenidate ER (Concerta, Ritalin, Metadate) but not with Amphetamine ER (Adderall XR).

That’s bizarre. I estimate the potential for abuse higher than for MPH.

❝ I was just wondering if EMA ask for it or not.

Ready for some history? Get a & take your pills.

According to the current GL nothing specifically, only a general statement about dose dumping:

If the modified release formulation contains a higher dose compared to the approved immediate release product, the possibility of unexpected release resulting in unacceptable higher exposure should be excluded.

But GLs are variable constants (© ElMaestro).

The Q&A (since Rev. 1 July 2009):

One issue that is important to consider for both new MR formulations and generic MR formulations is the influence of alcohol on the MR formulation and the risk for unexpected release caused by alcohol ingestion.

Two years ago I attended a scientific advisory meeting at the German BfArM about a new dexamfetamine ER product (not a generic; only IR marketed in the EU). We talked about alcohol induced dose-dumping and their answer was a “positive maybe”. They made clear that before the new GL is applicable, every European member state would decide on a case-by-case basis. BTW, I think that there is no generic version of Adderall XR marketed in the EU (though, I didn’t check).

The 2013 draft GL (Section 6.9):

For generic oral formulations, in vitro studies of the release in alcohol solutions should be performed. Where accelerated active substance release is seen in vitro either at high or low alcohol concentrations over a short period of time or at lower alcohol concentrations over a longer period of time, the product should be reformulated.
If the alcohol effect cannot be avoided and it is present also in the reference product, the applicant should justify / demonstrate that it lacks of clinical relevance.

For what was discussed in Bonn last June, see this post and presentations by Jan Neuhauser and Andrzej Dzierbicki. Currently alcohol testing seems to be a hobby of regulators from Spain and France whereas others simply don’t care.