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.
In this series of articles on generic medications, I described how generic drugs are defined and regulated by the U.S. Food and Drug Administration (FDA), how the concepts of bioavailability and bioequivalence are essential to understanding generic drug development, and how the distinction between pharmaceutical equivalent and alternative drug products is important to understand (Howland 2009, 2010a, 2010b). Because multiple branded, alternative, and generic medications contain the same active ingredient, controversies sometimes arise regarding generic substitution. For patients, physicians, and nurses, the bottom-line issue is whether generic medications are safe and effective. In this article, I will address this issue and discuss how expectancy theory may explain problems associated with generic substitution.
All of the most commonly used antidepressant drugs in the United States were introduced since 1986, and it is only in recent years that generic substitutes have become available for many of them. The greatest controversy with regard to generic substitution has been reported with the drug bupropion hydrochloride (Wellbutrin®). Bupropion hydrochloride tablets (Wellbutrin), bupropion hydrochloride sustained-release tablets (Wellbutrin SR®), and bupropion hydrochloride extended-release tablets (Wellbutrin XL®) are pharmaceutical alternative antidepressant drugs (Howland, 2010b). Multiple generic versions (made by different manufacturers) for each of these brand-name formulations of bupropion hydrochloride have been approved by the FDA. Budeprion SR and Budeprion XL are particular “brand-name” generic versions (manufactured by Teva Pharmaceuticals) of Wellbutrin SR and Wellbutrin XL, respectively.
During the first 6 months of 2007, the FDA received 85 postmarketing reports in which patients who switched from Wellbutrin XL 300 mg to Teva’s Budeprion XL 300 mg formulation experienced an undesirable effect (FDA, 2009). In 78 of these reports, there was a reported loss of antidepressant effect following a switch from the Wellbutrin to the Budeprion product. In addition to the loss of effect, several patients also reported the new onset or worsening of side effects. More than half of the patients who switched back to Wellbutrin XL 300 mg reported improvement of depression or an abatement of side effects. To evaluate these reports, the FDA reexamined the data on the bio-equivalence of Wellbutrin XL 300 mg and Budeprion XL 300 mg. Although there were small differences between products in the rate of absorption (the maximum drug concentration, Cmax) and the extent of drug absorption (the resulting area under the plasma concentration-time curve, AUC), the differences did not fall outside of the established guidelines for bioequivalence (“Wellbutrin,” 2008).
In 2007, approximately 1 million prescriptions per month were dispensed for all bupropion XL versions (“Wellbutrin,” 2008). Definitively establishing causality to a generic switch on the basis of uncontrolled postmarketing reports simply cannot be done. To further investigate these postmarketing reports and to better account for potential confounding factors, several prospective randomized clinical bioequivalence trials have been initiated, comparing various branded and generic formulations of bupropion hydrochloride ( http://www.clinicaltrials.gov).
Paroxetine hydrochloride tablets (Paxil®) and paroxetine mesylate (Pexeva®) are pharmaceutical alternative antidepressant drugs because they have the same active ingredient, but they are not generic substitutes (Howland, 2010b). A published report describing adverse effects in two patients after switching to a different “generic form” of paroxetine (i.e., after switching from paroxetine hydrochloride to paroxetine mesylate) is therefore misleading (Vergouwen & Bakker, 2002). Multiple generic versions of Paxil have been approved by the FDA, and there are no reports about efficacy or tolerability problems.
Venlafaxine hydrochloride extended-release capsules (Effexor XR®) and venlafaxine hydrochloride extended-release tablets (venlafaxine ER tablets, marketed by Osmotica Pharmaceuticals) are pharmaceutical alternative antidepressant drugs, but they are not generic substitutes (Howland, 2010b). A recent publication comparing the pharmacokinetic profiles of “brand-name” and “generic” formulations of venlafaxine (i.e., Effexor XR capsules and venlafaxine ER tablets) reported that these two formulations were not bioequivalent and had different rates of side effects (Chenu et al., 2009). However, because Effexor XR capsules and venlafaxine ER tablets do not have any approved generic versions, this report is misleading.
Many anticonvulsant drugs are used for the treatment of various mental disorders, but the greatest controversy with regard to generic substitution has been reported when the drugs are used in the treatment of epilepsy. Some, but not all, retrospective case-control and cohort studies found that switching between brand-name and generic versions of various anticonvulsant drug products was associated with seizure breakthroughs and other complications, although no prospective randomized controlled studies have demonstrated therapeutic inequivalence (Borgherini, 2003; Devine, Weisbart, Barron, & Behm, 2010; “Generic Drugs,” 2009). However, because small variations in concentrations between brand-name and generic anticonvulsant drugs can cause toxic effects or seizures in patients with epilepsy, the American Academy of Neurology (2006) has stated its opposition to automatic generic substitution of anticonvulsant drugs for the treatment of epilepsy without the approval of the patient’s treating physician.
Although generic substitution concerns have not been frequently raised with the use of anticonvulsant drugs for treating mental disorders, nurses should be aware in particular of the differences in bioavailability between divalproex sodium delayed-release tablets (Depakote®) and divalproex sodium extended-release tablets (Depakote ER®) (Howland, 2010b). These drugs are not generic equivalents, but they are often exchanged in clinical practice. The bioavailability of Depakote ER is substantially less than Depakote (by approximately 25%). For this reason, patients switched from Depakote would need to take a conversion dosage of Depakote ER that is 25% higher. Conversely, patients switched from Depakote ER would need to take a conversion dosage of Depakote that is 25% lower. If these formulations are switched using the same dosage, breakthrough symptoms or adverse effects can occur.
Among the many available first generation (typical) and second generation (atypical) antipsychotic drugs, clozapine (Clozaril®, FazaClo®) is the only one that has been frequently associated with concerns about generic substitution (Borgherini, 2003; Oluboka, Stewart, Landry, & Adams, 2010). Some, but not all, of these uncontrolled studies reported problems with clinical deterioration or adverse effects when the brand-name drug was switched to a generic version. Most recently, a prospective randomized blinded study did not demonstrate any clinical deterioration in patients switched from brand-name clozapine (Oluboka et al., 2010).
Expectancy Theory and Generic Drugs
Uncontrolled reports of problems associated with generic switches are subject to many confounding factors and biases. The drug products look different, and some patients may be biased or skeptical about being switched to generic alternatives. In addition, given the natural history of depression and other illnesses, relapses may occur regardless of whether a particular brand is continued or switched. The concept of expectancy has been used to explain placebo and nocebo effects (Brody & Brody, 2000; Stewart-Williams & Podd, 2004), and this might be relevant to understanding or explaining patients’ experiences in switching medications.
Expectancy theory proposes that the conscious or unconscious expectations or beliefs that patients have about treatment will influence how they respond or react to treatment. Patients who have positive expectations that treatment will help them demonstrate a significantly higher level of response to an active medication compared with those patients with less positive expectations taking the same medication (Krell, Leuchter, Morgan, Cook, & Abrams, 2004). Patients with positive expectations may therefore get better even if they are taking a placebo.
By contrast, negative expectations may have a deleterious effect. As a result, some patients may develop noxious adverse effects with a placebo. This effect has been termed the nocebo effect (Barsky, Saintfort, Rogers, & Borus, 2002). Similarly, positive or negative expectations harbored by treatment providers (including physicians and nurses) may subtly (or not so subtly) affect what patients believe will happen with treatment, and this may contribute to placebo and nocebo effects.
Relapses temporally associated with switches from brand-name to generic drugs could be due to the change but could also be explained partly as a loss of the positive expectations of treatment accompanied by a fear that generic is inferior to brand name. For example, a double-blind study of healthy volunteers found that the perception of the price of treatment influenced the analgesic response to placebo given for experimentally induced pain (Waber, Shiv, Carmon, & Ariely, 2008). All participants were told that they would be receiving a newly approved opioid analgesic drug but actually were given a placebo. After randomization, half the participants were informed that the new drug had a regular price of $2.50 per pill, and half were told that the drug had been discounted to $0.10 per pill. Pain reduction was significantly greater for participants taking the regular price placebo.
Similarly, adverse effects temporally associated with medication switches could be attributed to the change but might also be explained as a kind of nocebo effect. Randomized controlled blinded studies are necessary to rigorously evaluate causality between generic switches and relapses or adverse effects. When such studies have been conducted, they typically have not confirmed uncontrolled reports that the safety or effectiveness of brand-name and generic drugs differ.
Despite sporadic claims and reports, there is no clear, convincing, or consistent evidence that generic substitutes are less safe or less effective than brand-name equivalents. Obviously, it is still clinically prudent to monitor a patient whose medication has been switched. Nurses in clinical practice should be able to use the information described in this series of articles to counsel patients and families about the safety and effectiveness of generic medications.
- American Academy of Neurology. (2006). Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Retrieved from http://www.aan.com/globals/axon/assets/2323.pdf
- Barsky, A.J., Saintfort, R., Rogers, M.P. & Borus, J.F. (2002). Nonspecific medication side effects and the nocebo phenomenon. Journal of the American Medical Association, 287, 622–627. doi:10.1001/jama.287.5.622 [CrossRef]
- Borgherini, G. (2003). The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clinical Therapeutics, 25, 1578–1592. doi:10.1016/S0149-2918(03)80157-1 [CrossRef]
- Brody, H.B. & Brody, D. (2000). Three perspectives on the placebo response: Expectancy, conditioning, and meaning. Advances in Mind-Body Medicine, 16, 216–232.
- 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]
- Devine, S.T., Weisbart, E., Barron, J. & Behm, A. (2010). Acute epilepsy exacerbations in patients switched between A-rated anti-epileptic drugs. Current Medical Research and Opinion, 26, 455–463. doi:10.1185/03007990903488704 [CrossRef]
- Generic drugs revisited. (2009). Medical Letter on Drugs and Therapeutics, 51(1323), 81–82.
- 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. (2010a). 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]
- Howland, R.H. (2010b). When is a “generic” medication not really a generic? Confusion about medication products containing the same active ingredient. Journal of Psychosocial Nursing and Mental Health Services, 48(2), 13–16. doi:10.3928/02793695-20100108-04 [CrossRef]
- Krell, H.V., Leuchter, A.F., Morgan, M., Cook, I.A. & Abrams, M. (2004). Subject expectations of treatment effectiveness and outcome of treatment with an experimental antidepressant. Journal of Clinical Psychiatry, 65, 1174–1179.
- Oluboka, O., Stewart, S., Landry, S. & Adams, S. (2010). Does therapeutic equivalence follow bioequivalence? A randomized trial to assess clinical effects after switching from Clozaril to generic clozapine (Gen-Clozapine). Journal of Clinical Pharmacology. Advanced online publication. doi:10.1177/0091270009347871
- Stewart-Williams, S. & Podd, J. (2004). The placebo effect: Dissolving the expectancy versus conditioning debate. Psychological Bulletin, 130, 324–340. doi:10.1037/0033-2909.130.2.324 [CrossRef]
- U.S. Food and Drug Administration. (2009). 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.
- Waber, R.L., Shiv, B., Carmon, Z. & Ariely, D. (2008). Commercial features of placebo and therapeutic efficacy. Journal of the American Medical Association, 299, 1016–1017. doi:10.1001/jama.299.9.1016 [CrossRef]
- Wellbutrin versus generic bupropion. (2008). Medical Letter on Drugs and Therapeutics, 50(1290), 54–55.