FDA Drops a Bombshell on Slow-Release Generic Drugs

The Food and Drug Administration’s announcement last week that two generic Concerta formulations might not work as well as the brand name medication has rekindled questions about the FDA’s generic drug approval process.

The long-acting generics are made by Mallinckrodt and Kudco. According to the FDA, the generic drugs delivered the active medicine methylphenidate at a slower rate than the brand name Concerta. This could have important implications for patients.

The mainstream media did not perceive the story as very exciting or worthy of the public’s attention. And yet this generic drug alert is likely to have far-reaching consequences for the generic drug industry.

The History of Methylphenidate

Concerta is the brand name for a stimulant drug called methylphenidate.

Methylpehnidate was originally approved by the FDA under the brand name Ritalin in 1955 for treating hyperactivity, what later became known as ADHD (attention deficit hyperactivity disorder). The problem with Ritalin was that the original formulation was relatively short acting. This meant that the benefits of the drug wore off after three to five hours. Doctors often prescribed two to three pills a day to be taken before meals.

This was inconvenient, especially for kids in school. Slow-release (SR) and long-acting (LA) formations were created, but each had some drawbacks. Ultimately, an extended-release formulation was created that provided a controlled rate of medicine for a long period of time.

OROS, a Unique Controlled-Release Delivery System

Concerta, an extended-release formulation of methylphenidate, got the green light from the FDA for ADHD in 2000. It was designed to provide active medication for 12 hours. The formulation was unique in that it used the OROS delivery system.

OROS stands for Osmotic [controlled] Release Oral System. It is a sophisticated gradual-release system that works because of a laser hole in the tablet. As the drug moves through the digestive tract, water enters the permeable membrane surrounding the tablet. The pressure created by the added water gradually pushes the active drug out through the laser hole.

Concerta lost its patent in 2011.

Generic formulations of extended-release methylphenidate ER could not use the OROS system because it was a patented process, although an authorized generic sold by Actavis apparently uses the identical OROS delivery system.

Authorized Generics

Authorized generics are licensed from the brand name manufacturer. They use identical active and inactive ingredients and are often made on the same production line as the brand name medication. They use the same formulation and delivery system as the branded product.

Other generic manufacturers have to come up with their own formulation that will, in theory, mimic the brand name process of releasing the active drug into the body. We have learned that is not always the case.

The Budeprion XL 300 Boondoggle

Early in 2007 we detected a problem with the generic version of the antidepressant Wellbutrin XL 300. The generic formulation, Budeprion XL 300, contained the active drug bupropion. The chemical was the same but the formulation was quite different. Wellbutrin XL 300 used a  membrane technology to get the drug into the body. The generic used a maxtrix technology, which released the medication substantially faster than the brand name.

Hundreds of visitors to this website reported side effects with the generic that they never had with the brand name. They also noted that the generic did not relieve their depression adequately. We badgered the FDA for years about its approval of the generic formulation. Eventually, the FDA conducted its own tests and agreed that the generic was not bioequivalent to the brand name and had Budeprion XL 300 removed from the market in October, 2012.

The Generic Concerta Controversy

Generic manufacturers of extended-release methylphenidate needed to develop their own special technology to produce a long-acting 12-hour effect. They couldn’t duplicate the OROS delivery system. Physicians, pharmacists, insurance companies and patients assumed they had been successful because their products passed the FDA’s bioequivalence testing standards. But then came reports of problems.

“To me the biggest fraud is when generic companies are allowed to change the dispersal method of a pill and still call them equivalent. This was the problem with generic Wellbutrin XL. I noticed almost immediately that the Teva generic [Budeprion XL 300] just didn’t work.

“I’m having the same problem with my husband’s Concerta ER. He noticed the problem the very first day. He said ‘it’s not as bad as taking nothing but it’s not nearly as good either.’ The first generic was actually a re-branding of the brand name, which was fantastic for us. But now, other companies have developed methylphenidate ER pills. The dispersal method is different on the new ones. They don’t have the same coating! Again!

“I fail to see how these can be considered equivalent. If they’re going to make a methylphenidate extended release with a different dispersal method they should be required to NOT call it generic for Concerta ER. And since I’ve learned from the Wellbutrin fiasco, I have called all over again looking for the original ‘generic.’ One pharmacy in the area carries it, because it’s more expensive to stock. I bet everyone is surprised by that, huh?

“My main point is that it took me a lot of phone calls and a lot of experience to figure this stuff out. How can we possibly expect everyone to be able to do what I managed to? Seniors who are starting to have memory problems? People who just plain don’t know it’s a possible problem? People with three jobs who don’t have the time to call 8 different pharmacies every time they get a refill?

“It’s disgusting, and I personally find it reprehensible that we allow the race to the bottom price to have priority over people’s welfare.” C.M.

The Bottom Line

The FDA has now acknowledged that its approval process for the extended-release form of generic Concerta was, in essence, flawed. The agency apparently received a number of complaints, just as we did. Additional analysis and laboratory tests convinced the FDA it had a problem, which is why it issued the “concern” about the Mallinkrodt and Kudco generic methylphenidate products. The Actavis authorized generic is made by the brand name manufacturer of Concerta and is, in fact, bioequivalent.

What are we to make of this entire mess? For us, the issue goes far beyond Budeprion XL 300 or generic forms of Concerta. The rules and regulations that the FDA relied upon for decades to approve long-acting generic formulations was, in our opinion, flawed. It did not take into account hour-to-hour blood levels but lumped everything together into something called the AUC (area under the curve). This allowed the FDA to approve generic drugs that actually performed quite differently from the brand name product they were supposed to be mimicking.

Although the FDA has maintained for years that generic drugs are “identical” to their brand name counterparts, that is clearly not the case. And the FDA seems to be gradually acknowledging that. The agency has  revised its rules regarding generic approval of extended-release preparations. We think our visitors are partially responsible for this change. The only problem is that hundreds of older timed-release generic products remain on the market. They were approved under the old “guidance.” We just do not know how well they are working or if they would pass muster under the new regulations.