Editor’s Note: The FDA issued a statement on November 13, 2014 addressing concerns regarding the therapeutic equivalence of the two most recently approved generic versions of Concerta tablets. Excerpts from this week’s statement regarding the Mallinckroft and Kudco versions of generic Concerta are featured below in blue…

Based on an analysis of data, FDA has concerns about whether or not two approved generic versions of Concerta tablets (methylphenidate hydrochloride extended-release tablets), used to treat attention-deficit hyperactivity disorder in adults and children, are therapeutically equivalent to the brand-name drug. The two approved generic versions of Concerta are manufactured by Mallinckrodt Pharmaceuticals and Kudco Ireland Ltd…

An analysis of adverse event reports, an internal FDA re-examination of previously submitted data, and FDA laboratory tests of products manufactured by Mallinckrodt and Kudco have raised concerns that the products may not produce the same therapeutic benefits for some patients as the brand-name product, Concerta, manufactured by Janssen Pharmaceuticals, Inc. Janssen also manufactures an authorized Concerta generic, which is marketed by Actavis under a licensing agreement and is identical to Janssen’s Concerta. FDA included the authorized generic in its analysis and found it to be bioequivalent to, and substitutable for, Concerta. Apart from the Mallinckrodt, Kudco, and Actavis products, there are no other generics for Concerta.

Methylphenidate hydrochloride extended-release products approved as generics for Concerta are intended to release the drug in the body over a period of 10 to 12 hours. This should allow for a single-dose product that is consistent with the effect of a three times per day dose of immediate-release methylphenidate hydrochloride.

In some individuals, the Mallinckrodt and Kudco products may deliver drug in the body at a slower rate during the 7- to 12-hour range. The diminished release rate may result in patients not having the desired effect.

As a result, the FDA has changed the therapeutic equivalence (TE) rating for the Mallinckrodt and Kudco products from AB to BX. This means the Mallinckrodt and Kudco products are still approved and can be prescribed, but are no longer recommended as automatically substitutable at the pharmacy (or by a pharmacist) for Concerta.

Consequently, FDA has revised its draft guidance for industry for bioequivalence testing for methylphenidate hydrochloride extended-release tablets (Concerta). FDA has asked that within six months, Mallinckrodt and Kudco confirm the bioequivalence of their products using the revised bioequivalence standards, or voluntarily withdraw their products from the market.

FDA will continue to evaluate its testing and approval standards and bioequivalence guidances for other generic methylphenidate hydrochloride extended-release products and revise as needed.

I’d ask our regular blog readers to allow me to digress today while I share some information about a medication issue that is greatly impacting many of the kids and families we serve.

Concerta is the most commonly prescribed medication to teens in the United States. When  the product first hit the market in 2000, it revolutionized the treatment of ADHD because Concerta offered the first truly effective method for prolonging the effects of methylphenidate (the active ingredient in Ritalin and many other stimulant preparations) so that kids no longer needed to go to the principal’s office or nurses’ office in the middle of the school day. When Adderall XR followed in 2001 and Strattera in 2002, a vast increase ensued in the number of children and teens identified with and treated for ADHD. Out of the roughly 25 medications approved for ADHD, Concerta remained very popular because of the consistency of its’ effects throughout the school day into the time immediately following school. It is widely used in teenagers because of its’ beneficial effects on driving performance.

A basic principle in understanding how extended-release stimulant products work is that the manner in which the drug is released into the body (the drug delivery system) has profound effects on the pharmacodynamics (the observed benefits/response to the drug). We have quite a number of approved medications for ADHD in which methylphenidate is the active ingredient. In addition to Concerta, Ritalin LA, Metadate CD, Daytrana, Quillivant and Focalin XR are all extended-release methylphenidate products. The effects of the medication at specific times throughout the day result from the differences in how the medication is released and absorbed into the body with each unique delivery system, and form the basis of how we decide which product we choose for an individual child. Allow me to illustrate…

Concerta utilizes something called the OROS delivery system (see featured picture at the top of this blog post) to release methylphenidate into the body. It was developed by a team of scientists in California who observed a phenomena referred to as “tachyphylaxis” with earlier attempts to develop long-acting methylphenidate-based stimulants. Essentially, people taking stimulants develop some degree of tolerance to the drug acutely in response to an individual dose. While the absolute level of the drug in someone’s system matters, whether the blood level is rising or falling also matters, since a rising blood level contributes to the ability of a stimulant to sustain beneficial effects over the course of a school or work day.

Concerta was designed to release an initial dose of stimulant within the first two hours of ingestion…22% of the active drug is contained within the coating of the pill. After this overcoat dissolves, a laser-drilled hole in the end of pill is uncovered. As the pill passes through the stomach and the gastrointestinal track, water taken up into the pill results in changes in internal pressure that leads to a “pulse release” of small amounts of medication as it passes through the gut. The effects of Concerta were tested in a laboratory classroom setting, in which raters blinded to whether kids received active drug or placebo scored the observable behavior of kids throughout a twelve hour day, and an age-appropriate mini-math test (PERMP) was administered at intervals throughout the day to measure the effects of medication on cognitive performance. The results are pictured below. A significant benefit of Concerta is the consistency of improvement in cognitive performance throughout the day.

In contrast, Focalin XR utilizes a “beaded” delivery system to release methylphenidate into the body. Focalin XR is a capsule containing two types of beads. The outer coating of the capsule dissolves very quickly (within ten minutes) upon ingestion. 50% of the beads inside Focalin XR release almost immediately after the coating of the outer capsule dissolve, while another 50% have a different coating designed to dissolve approximately four hours after the capsule is swallowed. One advantage of Focalin XR is that parents can crack open the capsule and sprinkle the contents in yogurt or applesauce when kids can’t swallow pills, whereas Concerta won’t work if the pill isn’t swallowed intact. Another advantage with 50% of the medication released immediately is that the medication kicks in very quickly in the morning with demonstrable benefits at 30 minutes (see below). In practice, Focalin XR has a pronounced peak effect in late morning and is very effective for most kids throughout the school day. At the same time, the cognitive effects of the drug fall off much more quickly during the latter part of the day compared to Concerta, and drug company marketing claims aside, I find in my patients that Focalin XR is a good choice for kids who need medication to cover the duration of their school day, but not much longer.

Daytrana is a patch worn on the hip in which methylphenidate is absorbed through the skin as a result of an osmotic gradient…the difference in the concentration of methylphenidate in the patch vs. the difference in the concentration of methylphenidate in the capillaries supplying blood to the skin. A unique benefit of Daytrana is that it will last longer than any of the other stimulant products on the market…it was originally developed to be a 16-18 hour drug. Because the testing required for approval by the FDA examined the effects of the product over a twelve hour period, the company that manufactures Daytrana isn’t permitted to share that information with prescribers. The cognitive effects of Daytrana also peak later in the day than with other products (see below), making Daytrana very helpful for many kids who struggle with homework after school. Comparing the laboratory classroom studies of Daytrana to Concerta and Focalin XR, an obvious downside to Daytrana is that it doesn’t work as well during the first half of the school day. Many parents resort to either putting the patch on their child very early in the morning while they’re still sleeping to overcome this effect, or give their child a small dose of immediate-release methylphenidate (Ritalin or immediate-release Focalin) when they first put the patch on in the morning.

My point is that what makes Concerta work like Concerta is the OROS delivery system. The same drug (methylphenidate) released through a different delivery system produces a VERY different response.

The arrival of generic Concerta was delayed for a number of reasons…the makers of Concerta fought the lawsuits of the generic manufacturers aggressively, and pursued a legal strategy involving what’s referred to as a “Citizen’s Petition” requiring generic companies seeking to copy Concerta to demonstrate a similar pattern of ascending blood levels throughout the day. Because Johnson & Johnson (the parent company that owned the rights to Concerta) owned the patent on the OROS release system, companies seeking to make a generic version had to do so with a different delivery system.

Ultimately, Watson Pharmaceuticals (subsequently acquired by Actavis) was approved to manufacture a generic equivalent of Concerta. As often occurs in these situations, the lawyers for Johnson & Johnson  and Watson worked out a deal to avoid years of legal battles in which J & J would continue to manufacture Concerta through their Alza subsidiary that Watson would sell at a discount as an “authorized generic,” with the two companies splitting the profits. The brand Concerta and the Watson/Activis version of Concerta are equivalent…they are manufactured in the same factory, using the same equipment and the same drug delivery system as in the original Concerta. Pictures of the “authorized generic” using the OROS system are shown above:

The last two versions of versions of generic Concerta (manufactured by Mallinkcrodt and by Kudco) each use very different drug delivery systems (release mechanisms) in an effort to replicate the therapeutic effect of Concerta.

In the case of the Mallinkcrodt product (pictured at right), an overcoat containing immediate-release methylphenidate that dissolves within the first hour after ingestion. The core of the pill contains a diffusion-controlling membrane that releases methylphenidate as water in the gastrointestinal tract passes through the membrane. The membrane is designed to release methylphenidate over a period of time roughly corresponding to the release period resulting from the OROS delivery system in Concerta.

The Kudco generic (pictured at right) uses an extended-release bead technology to release methylphenidate at a controlled rate. The pill resembles a conventional tablet in appearance, featuring an overcoat containing immediate release stimulant that releases during the first hour as the tablet disintegrates and a core of extended-release stimulant beads operating with a similar mechanism as those in Focalin XR.

So, how do these products compare to the original Concerta? We don’t know! Here are links to the FDA-required product information or “labels” for Concerta, the Mallinkcrodt generic version and the Kudco generic version that are being substituted for Concerta. It appears that the FDA allowed the generic manufacturers to “cut and paste” the data from Concerta’s pharmacokinetic studies and clinical trials and present this information as if it represented trials each company conducted with their own unique product. It’s EXTREMELY UNLIKELY that different drug delivery systems would produce EXACTLY the same results in terms of drug metabolism (pharmacokinetics) and drug effects (pharmacodynamics) as the brand name drug.

The absorption of the original Concerta depends to some degree on an individual’s GI transit time…i.e., how long it takes for the pill to pass through the gut. Bead release systems (as in the Kudco version) typically depend upon the acidity of the contents of the stomach at the time the extended-release bolus of medicine is needed. One would anticipate an individual child or teen might absorb significantly more (or less) medicine at different times during the day when two products that on average deliver roughly the same amount of medication over the same time period depend upon different physiologic processes.

When the FDA requires generic companies to do studies demonstrating “equivalency” to a brand medication, the amount of medication taken up into the body (measured by what we refer to as the “area under the curve” or AUC) is required to be within 80-125% of that observed with brand name drug. With some types of medication, that variability makes little difference. With stimulants, small differences in either the rate at which the medicine is absorbed or the time at which the medicine is absorbed make a PROFOUND difference in the benefits or side effects experienced by an individual child or adult. The FDA doesn’t require generic companies to conduct comparison studies showing that the products work as well in practice as the brand name drugs they’re intended to replace. Neither Mallinkcrodt nor Kudco has been required by the FDA to conduct a study showing that their drug works as well in practice as the brand or authorized generic versions of Concerta.

Restating my earlier point, what makes Concerta work like Concerta is the OROS delivery system. The same drug (methylphenidate) released through a different delivery system produces a VERY different response.

In my mind, this is an utter and complete outrage when we’re talking about the most commonly prescribed drug for teenagers in the United States. I’d argue that this is a social justice issue. I’ve now had over ten kids come into my office for follow-up since the first of the year who have reported a significant decline in the effectiveness of their medication in the last couple of months. One nationwide drug store chain began ordering the Kudco product (the version many of my families have found to be less effective…the two main complaints being it doesn’t work as well or last as long as the original) in large quantities several months ago and substituting it for the authorized generic version of Concerta. What put me over the edge was an experience yesterday when I saw a mother and her daughter who reported problems with her medication since the appearance of her pill had changed. I sent them to the drugstore with new prescriptions for the brand Concerta or the authorized generic version. The mother was told by the pharmacy that it was illegal for them to fill the prescription for the original product even though she was willing to pay for the prescription “out of pocket” and that they would call the police if she insisted on having the prescription filled.

I’m at the end of my rope as a result of the administrative hassles involved with getting the kids in my practice the medications and educational support services they need to thrive in school, at home, with their friends and in community activities. I can’t even imagine what life must be like when parents have little money and need to depend upon our systems of care for support.

Here’s a link to the FDA’s Medwatch website, where health professionals and consumers can report problems with prescription drugs. If consumers experiencing problems with specific versions of generic medications inundate the FDA with reports of their experiences, there’s a greater chance action will be taken to further scrutinize the safety and effectiveness of those products. If you or your child are experiencing unanticipated effects from ADHD medication, please file reports with the FDA for the sake of others who may be experiencing similar effects.

Portions of this article were originally published on February 23, 2014

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Key Ministry has assembled a helpful resource page for church leaders and parents addressing the topic of ADHD and spiritual development. This page includes our blog series on the topic and links to helpful videos and resources for pastors, church staff, volunteers and parents. Access the resource page here.