Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
The concept of bioequivalence is used by the U.S. Food and Drug Administration (FDA) to evaluate and approve generic drugs (therapeutic equivalents) without additional safety and efficacy studies (Howland, 2009, 2010). However, pharmaceutical alternative drugs also are sometimes approved by the FDA on the basis of bioequivalence studies and without necessarily conducting safety and efficacy studies. The distinction between pharmaceutical equivalent and pharmaceutical alternative drug products, described in the two previous Psychopharmacology articles (Howland, 2009, 2010), can lead to considerable confusion with respect to the proliferation of various branded, alternative, and generic medications. In this month’s article, several examples will be described that should alert nurses to the need to understand the difference between pharmaceutical equivalent and pharmaceutical alternative drug products.
Paroxetine hydrochloride (HCl) tablets and liquid (Paxil®, Paxil Oral Suspension) and paroxetine HCl extended-release tablets (Paxil CR®) are pharmaceutical alternative antidepressant drugs. Paxil (tablets) was approved with labeled indications for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and posttraumatic stress disorder (PTSD). Each of these indications was based on clinical safety and efficacy studies. On the basis of bioequivalence data with Paxil tablets, Paxil Oral Suspension was later approved with the same approved indications. Paxil CR was developed based on bioequivalence studies with Paxil tablets, but additional clinical safety and efficacy studies of Paxil CR were conducted, resulting in labeled indications for MDD, PD, SAD, and premenstrual dysphoric disorder. Generic versions of Paxil tablets, Paxil Oral Suspension, and Paxil CR have been approved based on bioequivalence studies; each particular generic formulation has the same labeled indications as does its brand-name counterpart.
Paroxetine mesylate (Pexeva®) is a pharmaceutical alternative to the various paroxetine HCl brand-name and generic products, because it has the same active ingredient (paroxetine). Pexeva is a brand-name product approved as a new drug with labeled indications for MDD, OCD, PD, and GAD as a result of clinical safety and efficacy studies. Pexeva has not been approved in any generic versions, and it is not a generic substitute for Paxil (Vergouwen & Bakker, 2002).
Venlafaxine HCl tablets (Effexor®), venlafaxine HCl extended-release capsules (Effexor XR®), and venlafaxine HCl extended-release tablets (venlafaxine ER tablets, marketed by Osmotica Pharmaceuticals) are pharmaceutical alternative antidepressant drugs. (Note that drugs are formulated as capsules or as tablets depending on the objective: the chemistry of the active ingredient, ease of use, pharmacokinetic goals, tolerability, maintaining or extending product patent protection, and so forth.) Effexor (tablets) was initially developed and approved as a new drug with an indication for MDD. Effexor XR (capsules) was later developed as a different formulation of Effexor tablets on the basis of bioequivalence studies, but it was investigated in additional clinical safety and efficacy trials and was given labeled indications for MDD, SAD, GAD, and PD.
Most recently, venlafaxine ER tablets were approved as a pharmaceutical alternative drug as a result of bioequivalence studies comparing it to Effexor XR capsules (Chenu et al., 2009). One of four bioequivalence studies showed a significant bioequivalence difference that was not deemed to be clinically significant. Venlafaxine ER tablets were approved with labeled indications for MDD and SAD on the basis of the bioequivalence similarities to Effexor XR capsules, but no independent clinical safety and efficacy studies were conducted with this drug. Venlafaxine ER tablets should not be considered a generic substitute for Effexor XR capsules. Multiple generic versions of Effexor tablets have been approved by the FDA, but Effexor XR capsules and venlafaxine ER tablets do not have any approved generic versions.
Bupropion HCl tablets (Wellbutrin®), bupropion HCl sustained-release tablets (Wellbutrin SR®), and bupropion HCl extended-release tablets (Wellbutrin XL®) are pharmaceutical alternative antidepressant drugs. Wellbutrin was initially developed and approved as a new drug with an indication for MDD as a result of short-term safety and efficacy studies. Wellbutrin SR was later developed as a different formulation (pharmaceutical alternative) of Wellbutrin, and it was approved (based on bioequivalence studies) with an indication for MDD. Although it was not independently investigated in short-term clinical safety and efficacy studies, one long-term relapse prevention study was conducted.
Wellbutrin XL was then developed as yet another formulation (pharmaceutical alternative) of Wellbutrin and was approved based on bioequivalence studies with Wellbutrin and Wellbutrin SR. Wellbutrin XL was approved with an indication for MDD, but no independent safety and efficacy studies were conducted. However, Wellbutrin XL was additionally investigated in safety and efficacy studies and approved for the treatment of seasonal affective disorder.
Zyban® is a brand-name formulation of Wellbutrin HCl sustained-release tablets. Zyban is exactly the same compound as Wellbutrin SR, but it was investigated independently and approved separately only as a treatment for smoking cessation. Multiple generic versions for each of the four brand-name formulations of bupropion have been FDA approved based on bioequivalence studies.
Budeprion SR®, Budeprion XL®, and Buproban® are each particular “brand-name” generic versions (manufactured by Teva Pharmaceuticals) of Wellbutrin SR, Wellbutrin XL, and Zyban, respectively (FDA, 2009b). This manufacturer also has a generic version of bupropion HCl tablets (Wellbutrin), but this product does not carry a unique “brand name.” Similar to other generic drugs, these four Teva products were each approved by the FDA on the basis of bioequivalence studies in comparison to their Wellbutrin and Zyban counterparts.
Bupropion hydrobromide extended-release tablets (Aplenzin®) were approved by the FDA with an indication for MDD as a result of bioequivalence studies with Wellbutrin XL, but it was not independently investigated in safety and efficacy studies. Aplenzin is a brand-name pharmaceutical alternative drug that does not have any approved generic substitutes. It is not a generic version of Wellbutrin XL.
Various marketed products contain the chemical moiety valproate. Valproic acid capsules and syrup (Depakene®), valproic acid delayed-release capsules (Stavzor®), divalproex sodium delayed-release tablets and capsules (Depakote®), divalproex sodium extended-release tablets (Depakote ER®), and valproate sodium injectable (Depacon®) are pharmaceutical alternative drugs (FDA, 2009a). The active ingredient that is released when these products are administered is the valproate ion. When valproic acid is ingested or valproate sodium is injected, they dissociate chemically and release valproate ions. Divalproex sodium is a stable compound composed of equal amounts of sodium valproate and valproic acid; when it is ingested, it dissociates chemically and releases valproate ions.
It is important to note that valproate sodium refers only to the injectable formulation (Depacon and Depacon generics). Divalproex sodium (Depakote and Depakote generics) refers to the stable compound that is composed of sodium valproate and valproic acid. The distinction is important because mixing valproic acid capsules or syrup (Depakene) into a solution of Depacon (valproate sodium) would not create divalproex sodium (Depakote).
Divalproex sodium has been the most extensively investigated valproate product. Depakote (tablets) was developed and approved with labeled indications for epilepsy, bipolar mania, and migraine headaches on the basis of safety and efficacy studies for these indications. Depakote (capsules) was later approved based on bioequivalence studies but has a labeled indication only for epilepsy. Depakote ER (tablets) was approved, with labeled indications for epilepsy, bipolar mania, and migraines, as a result of bioequivalence studies with Depakote tablets, but additional safety and efficacy studies were conducted in bipolar mania and migraines.
The market introduction of Depakene, which has a labeled indication for epilepsy, predates that of Depakote, although bioequivalence studies have been conducted between the two products. No independent safety and efficacy studies of Depakene for bipolar mania or migraines have been conducted. Stavzor was more recently approved, with labeled indications for epilepsy, bipolar mania, and migraines, on the basis of bioequivalence studies with Depakote tablets. No independent safety and efficacy studies have been conducted with Stavzor.
Depacon injectable was approved, with a labeled indication as a temporary intravenous alternative to oral valproate products for epilepsy, as a result of bioequivalence studies with Depakote tablets. FDA-approved generic versions of Depakene (capsules and syrup), Depakote (tablets and capsules), Depakote ER, and Depacon injectable are available, but none are available for Stavzor.
The distinction between pharmaceutical equivalent and alternative drugs can be confusing, especially because there are now many branded, alternative, and generic medications that contain the same active ingredient. Only generic drugs can be freely substituted for a brand-name product. Switching to a pharmaceutical alternative requires a change in prescription. In addition, the use, labeling, and cost of branded, alternative, and generic medications may be different. Nurses who work with patients and families should be familiar with these distinctions. The Orange Book (FDA, 2009a) and Drugs@FDA ( http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm) are useful guides. Next month, in the last article of this series, I will address the issue of whether generic and brand-name medications really are equivalent.
- Chenu, F., Batten, L.A., Zernig, G., Ladstaetter, E., Hebert, C. & Blier, P. (2009). Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: A crossover study. Journal of Clinical Psychiatry, 70, 958–966. doi:10.4088/JCP.09m05315 [CrossRef]
- Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417. Retrieved from the Library of Congress website: http://thomas.loc.gov/
- Howland, R.H. (2009). What makes a generic medication generic?Journal of Psychosocial Nursing and Mental Health Services, 47(12), 17–20. doi:10.3928/02793695-20091103-99 [CrossRef]
- Howland, R.H. (2010). Evaluating the bioavailability and bioequivalence of generic medications. Journal of Psychosocial Nursing and Mental Health Services, 48(1), 13–16. doi:10.3928/02793695-20091204-07 [CrossRef]
- U.S. Food and Drug Administration. (2009a). Approved drug products with therapeutic equivalence evaluations (Orange book) (29th ed.). Retrieved from http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
- U.S. Food and Drug Administration. (2009b). Review of therapeutic equivalence generic bupropion XL 300 mg and Wellbutrin XL 300 mg. Retrieved from http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm153270.htm
- Vergouwen, A.C. & Bakker, A. (2002). Adverse effects after switching to a different generic form of paroxetine: Paroxetine mesylate instead of paroxetine HCl hemihydrate. Nederlands Tijdschrift voor Geneeskunde, 146, 811–812.