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  1. Drug Safety and Availability

Questions and Answers Regarding Methylphenidate Hydrochloride Extended Release Tablets (generic Concerta) made by Mallinckrodt and UCB/Kremers Urban (formerly Kudco)

What is methylphenidate hydrochloride extended-release?

Methylphenidate hydrochloride extended-release (ER) is a drug approved by FDA to treat attention deficit-hyperactivity disorder (ADHD) in adults and children ages six and older. Concerta is one brand of methylphenidate hydrochloride ER tablets. Concerta is manufactured and marketed by Janssen Pharmaceuticals, Inc. 

What are the generic versions of Concerta?

Approved generic versions of Concerta are manufactured by Mallinckrodt and UCB/Kremers Urban (formerly Kudco). Janssen also manufactures an authorized generic of Concerta, which is marketed by Actavis under a licensing agreement. Although it is marketed by Actavis as a generic and not under the Concerta brand name, the Actavis drug is identical to Janssen’s Concerta. 

When were the Mallinckrodt or UCB/Kremers Urban generic products approved by FDA?

Mallinckrodt received FDA approval of its abbreviated new drug application (ANDA) on December 28, 2012, for the 27-, 36-, and 54-milligram strengths. 

Kudco (now UCB/Kremers Urban) received FDA approval of its ANDA on July 9, 2013, for the 18- and 27-milligram strengths, and September 23, 2013, for the 36- and 54-milligram strengths.

How can patients find out which company manufactured their methylphenidate hydrochloride ER product?

Anyone with questions or concerns about where their methylphenidate hydrochloride ER product was manufactured should contact the pharmacy where the prescription was filled.

Will the generic methylphenidate hydrochloride ER made by Mallinckrodt or UCB/Kremers Urban be taken off the market or recalled?

FDA asked that within six months, Mallinckrodt and Kudco (now UCB/Kremers Urban) confirm the bioequivalence of their products using the revised bioequivalence standards, or voluntarily withdraw their products from the market. FDA changed the therapeutic equivalence (TE) rating for both companies’ products in Approved Drug Products with Therapeutic Equivalence Evaluations (commonly referred to as the “Orange Book”) from AB to BX.  This means that the data are insufficient to show that the products provide the same therapeutic effect as Concerta (or the authorized generic marketed by Actavis).  A drug with a BX rating is still approved and can be prescribed, but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug. 

Are other generic versions of Concerta methylphenidate hydrochloride ER available on the market?

Actavis continues to market an authorized generic version of Janssen’s Concerta under an agreement with the brand-name company. This product is called an “authorized generic” because it is manufactured by the brand-name company, but is marketed as a generic. The Actavis generic product is identical to Janssen’s brand-name Concerta.  FDA has not identified concerns with the Actavis or Janssen products. 

Does this action affect other currently approved methylphenidate hydrochloride ER products (e.g., Ritalin LA)?

No. This action only pertains to generic drugs that reference Concerta. It does not affect other methylphenidate hydrochloride ER products. 

How did FDA become concerned that Mallinckrodt and Kudco (now UCB/Kremers Urban) methylphenidate hydrochloride ER tablets may not be therapeutically equivalent?

FDA began to receive reports of lack of effect associated with the Mallinckrodt and Kudco (now UCB/Kremers Urban) generic methylphenidate hydrochloride ER products shortly after the initial approval of each product, in December 2012 and July 2013, respectively. Between May 2013 and June 2014, the FDA Adverse Event Reporting System (FAERS) database received reports of patients describing insufficient therapeutic effect. There were nearly 200 reports about the Mallinckrodt product and over 100 reports about the Kudco (now UCB/Kremers Urban) product. 

Although the total number of lack of effect reports with these two products is very small compared to the overall usage of the products, FDA evaluated the overall number of complaints for these two generic products relative to the brand-name and authorized generic products and found substantially more complaints for the two generic products – prompting FDA’s investigation into this issue.

After learning of concerns with the products, FDA’s Office of Generic Drugs conducted a multi-disciplinary review of the products, which included:

  • An evaluation of adverse event reports
  • A review of the data that were submitted with the ANDAs
  • Testing of the drug products in FDA labs, including drug stability and dissolution testing to determine the drug release rate and the stability of the two methylphenidate isomers and their degradation products
  • Broad interdisciplinary consultation with FDA physicians, pharmacists, chemists, and other agency scientists and experts to discuss the new information

Why didn’t FDA uncover this concern before approving these generic drugs?

Before approving any generic drug product, FDA requires many rigorous tests and procedures, in addition to the bioequivalence testing of the product against the reference listed drug (brand-name drug), to assure that the generic drug is substitutable for the brand-name drug. The original draft guidance recommendations for bioequivalence testing for this product (published in September 2012) were developed using the best information available at the time of issuance. This included, among other information, a comprehensive discussion of the issue by an FDA Advisory Committee on April 13, 2010.

In addition to tests performed prior to market entry, once approved, FDA regularly and thoroughly evaluates reports of alleged drug product inequivalence, such as lack of effect, as in this case. In some cases, such reports can lead to a re-evaluation of equivalence in light of new scientific approaches and methodology that have been developed subsequent to the initial draft guidance publication.

Mallinckrodt and Kudco (now UCB/Kremers Urban) provided data that met FDA’s approval standards at the time of approval, consistent with FDA’s best understanding of how to demonstrate bioequivalence to Concerta. The data showed the methylphenidate hydrochloride ER products to be bioequivalent to Concerta based on FDA’s understanding, at that time, of how the pharmacokinetics of Concerta contributed to the therapeutic efficacy.  

Do other generic versions of ADHD drugs on the market raise similar concerns?

At this time, there is no evidence that other generics in this class raise similar concerns. FDA will continue its monitoring of all generic drugs, and all products on the market, and welcomes any information from the public about the performance of drugs and any adverse effects.  

Will the generic methylphenidate hydrochloride ER made by Mallinckrodt or UCB/Kremers Urban (formerly Kudco) be taken off the market or recalled during the withdrawal proceedings?

FDA is proposing to withdraw approval of the Mallinckrodt and UCB/Kremers products because the sponsors have not demonstrated that their products are bioequivalent to Concerta under the revised recommendations provided in the draft guidance for industry.  

While the withdrawal proceedings are ongoing, the Mallinckrodt and Kremers products are still approved and can be prescribed, but are not recommended as automatically substitutable for Concerta.  If FDA withdraws the approval of a product, it can no longer be marketed.  The FDA has recently approved a generic version of Concerta sponsored by Mylan Pharmaceuticals.

Is FDA going to further study generic methylphenidate hydrochloride ER products?

The FDA and stakeholders have identified the study of generic methylphenidate hydrochloride ER tablets as a priority. Under the Generic Drug User Fee Amendments of 2012 regulatory science initiative, the FDA commissioned two studies: a bioequivalence study in healthy adult volunteers examining the Mallinckrodt product, which started in October 2014 and has been completed, and a pharmacokinetic and pharmacodynamic study in children with ADHD, which started in October 2014 and is expected to finish by September 2017.  In the completed bioequivalence study, it was found that the Mallinckrodt product did not satisfy the bioequivalence criteria with respect to Concerta. 

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