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Editorial

Recent Recall of a Generic Form of Extended-Release Paliperidone

Shader, Richard I. MD; Greenblatt, David J. MD

Author Information
Journal of Clinical Psychopharmacology: October 2017 - Volume 37 - Issue 5 - p 493-494
doi: 10.1097/JCP.0000000000000765
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Earlier this year, (May 31, 2017) Teva Pharmaceuticals USA, Inc issued a retail-level voluntary recall for a single batch of its generic, extended-release (ER) form of the oral antipsychotic agent paliperidone.1 This recall was then elevated to a consumer/user-level in a coordinated effort with the Food and Drug Administration (FDA). The recall involves a single, 360-bottle batch (lot number 1160682A). Each bottle contains ninety 3-mg pills. It is unlikely that anyone ingesting a pill or pills from this batch will be seriously harmed. Nevertheless, we believe there is heuristic value in examining and discussing the details of this recall.

The first point is a saga of mergers and acquisitions, a common practice in today's pharmaceutical space. This generic paliperidone was approved for marketing by the FDA on August 3, 2015.2 The submitting sponsor was Actavis Laboratories FL, Inc. This Florida-based company was a subsidiary of Actavis Generics. Actavis Generics was created from Watson Pharmaceuticals and Actavis, plc. Actavis Generics was given its name by Allergan, Inc. Actavis acquired Allergan in 2015, and later that year, in June, Allergan changed its name to Actavis. These morphings of Actavis actually began in 2012, when Watson purchased Actavis and took on the name Actavis.3 Then, in 2013, Actavis acquired Warner Chilcott. This merger was followed by the acquisition of Forest Laboratories in 2014. Actavis then purchased Allergan, Inc in 2015, and later that same year (again in June) it changed its name to Allergan. Allergan retained a subsidiary called Actavis Generics. The latter unit was then acquired by Teva Pharmaceutical Industries 1 year later (August 3, 2016).4 Teva now markets this paliperidone ER through its Actavis Generics component. The amalgamation of all of these generic companies has made Teva one of the largest generics manufacturers in the world. Perhaps it should not be surprising that when one of us (R.I.S.) called Teva (1-888-838-2872) to discuss the details of the recall, the courteous Teva information specialist indicated that no further information was available beyond what is stated in the recall notification. This statement was repeated again after the specialist consulted a supervisor.

The Teva product is a generic version of Janssen Pharmaceutical's OROS-based, ER product called Invega. Paliperidone is the active metabolite (9-hydroxyrispiridone) of another innovative drug from Janssen Pharmaceutical, the older atypical antipsychotic agent risperidone. Janssen Pharmaceutical's ER paliperidone was approved by the FDA in 2006. The product labels, as should be expected, are identical for both products5,6: peak plasma concentration (Cmax) after a single dose occurs at approximately 24 hours after ingestion; the elimination half-life is also approximately 24 hours, and bioavailability is 28%. It is important to remember that the determination of bioavailability is not easy, because it requires determining the total percentage of an oral dose that reaches the systemic circulation unmetabolized relative to plasma concentrations after intravenous administration of the same dose of the same drug.7 Paliperidone is available for intramuscular administration, but there is no marketed intravenous formulation.

Next let us reflect on the following sections taken from the Teva recall.1 “… this recall is being carried out due to failing test results for dissolution. Teva cannot at this time exclude the potential for additional tablets to be below specification… based on Teva's investigation, the likelihood of consuming 2 or more consecutive doses with affected product is low…” Dissolution testing follows strict guidelines. For readers interested on how dissolution testing is done, an up-to-date explanation is available from the United States Pharmacopeial Convention.8

The first point in the abstracted portion of the recall about which we wanted further clarification relates to the failed dissolution test. This product is not being used for its single-dose effects. It is not like a sedative-hypnotic for which dissolution and its links to time to peak concentration (Tmax), the concentration at Tmax (Cmax), and bioavailability are key determinants of onset and efficacy. For example, we have shown, for 2 different benzodiazepines, that how preparations are made (eg, particle size, excipients, coatings, solid versus capsule, etc) can have clinically important pharmacodynamic consequences.9–11 If the dissolution rate for ER paliperidone was merely slower, but nevertheless complete, perhaps there would be no clinical consequences. By contrast, if the pills were largely undissolved, passage of unabsorbed drug into the feces might have clinical consequences. Remember, though, that this is an ER drug for a chronic illness. We know that adherence is rarely perfect in most chronic conditions. Should missing the effects from a single pill really make a difference?

This takes us to our second observation. The statement is made that there is a low likelihood that a patient would consecutively consume 2 or more defective pills. No information is provided that supports this claim. If a patient has been given 1 of the 360 bottles, why might not all of the 90 pills be affected? We have to assume that Teva has information to support this statement. It is possible that no further testing was conducted; it may be less costly to the company to conduct a recall than to pin down the details of what actually happened and why.

We live in an era in which patients are being asked to be more active partners in medical decision-making. We are also in a climate where more generic drugs are, and will be, consumed to lessen the costs of medical care. Furthermore, some new drugs are being brought to market after less carefully studied patient exposure, both in numbers and in time. In addition, some policy makers wish to lessen the profile of the FDA and reduce regulatory controls. Our view is that postmarketing surveillance is even more important under these circumstances. We urge pharmaceutical companies to provide more information than they often do. We also hope that the Office of Pharmaceutical Quality within the FDA's Center for Drug Evaluation and Research will be given adequate funds to fulfill its mandates.12 It is also essential that the Center for Drug Evaluation and Research’s Division of Pharmacovigilance and its Office of Surveillance and Epidemiology be fully staffed and funded.13

AUTHOR DISCLOSURE INFORMATION

The authors declare no conflicts of interest.

REFERENCES

1. Food and Drug Administration. Teva pharmaceuticals, USA extends voluntary nationwide recall to consumer/user level for one lot of paliperidone extended-release tablets, 3 mg, 90 count bottles distributed under the Actavis Pharma Inc label due to dissolution test failure. Food and Drug Administration. Available at: https://www.fda.gov/Safety/Recalls/ucm563346.htm. Accessed July 1, 2017.
2. Food and Drug Administration. ANDA 202645. Department of Health and Human Services. Available at: https://www.tevagenerics.com/assets/base/products/fda/Pali_202-645.pdf. Accessed July 1, 2017.
3. Wikipedia. Actavis. Wikipedia. Available at: https://en.wikipedia.org/wiki/Actavis. Accessed July 1, 2017.
4. Teva Pharmaceutical Industries. Teva completes acquisition of Actavis Generics. Teva Pharmaceutical Industries. Available at: http://www.tevapharm.com/news/teva_completes_acquisition_of_actavis_generics_08_16.aspx. Accessed July 1, 2017.
5. Janssen. Invega. Janssen. Available at: http://www.janssencns.com/invega-prescribing-information. Accessed July 1, 2017.
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8. The United States Pharmacopeial Convention. <711>Dissolution (official December 1, 2011). Available at: http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/2011-02-25711DISSOLUTION.pdf. Accessed July 1, 2017.
9. Dreyfuss D, Shader RI, Harmatz JS, et al. Bioequivalence studies in the elderly: a pilot study of two oxazepam dosage forms. J Clin Psychopharmacol. 1987;7:200.
10. Dreyfuss D, Shader RI, Harmatz JS, et al. Kinetics and dynamics of single doses of oxazepam in the elderly: implications of absorption rate. J Clin Psychiatry. 1986;47:511–514.
11. Locniskar A, Greenblatt DJ, Harmatz JS, et al. Bioinequivalence of a generic brand of diazepam. Biopharm Drug Dispos. 1989;10:597–605.
12. Food and Drug Administration. FDA pharmaceutical quality oversight. April 14, 2015. Food and Drug Administration. Available at: www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm442666.pdf. Accessed July 1, 2017.
13. Food and Drug Administration. FDA post-marketing drug safety surveillance. Food and Drug Administration. Available at: https://www.fda.gov/downloads/AboutFDA/WorkingatFDA/FellowshipInternshipGraduateFacultyPrograms/PharmacyStudentExperientialProgramCDER/UCM544981.pdf. Accessed July1, 2017.
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