Antidepressants: Brand Name or Generic?

May 12, 2009

For many antidepressants, the issue of brand-name versus generic has no practical significance. Elavil was first marketed almost a half century ago, and its patent has long expired. It lives on, however, but as generic amitriptyline. Today, only a few antidepressants are still fully protected by patents, namely, Cymbalta (2010), Lexapro (2012), and Pristiq (2022) for major depressive disorder (MDD); and Seroquel (2011) and Symbyax (2017) for bipolar depression.

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For many antidepressants, the issue of brand-name versus generic has no practical significance. Elavil was first marketed almost a half century ago, and its patent has long expired. It lives on, however, but as generic amitriptyline. Today, only a few antidepressants are still fully protected by patents, namely, Cymbalta (2010), Lexapro (2012), and Pristiq (2022) for major depressive disorder (MDD); and Seroquel (2011) and Symbyax (2017) for bipolar depression.

The issue of brand-name versus generic, however, is far more complex than merely listing patent expiration dates. Patents can be extended, challenged, and infringed on; financial considerations are enormous; and patient care issues are often of central importance. To place antidepressants in proper perspective, it is first necessary to provide some general background about patents and drug regulation.

Background
Our patent system had its birth in the United States Constitution, which gave Congress power “To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries” (US Constitution, Article 1, Section 8, Clause 8). Shortly thereafter, the US Patent and Trademark Office came into existence.1

Meanwhile, regulation and oversight of pharmaceuticals was evolving (Table 1)-particularly with

the passage of the Pure Food and Drug Act of 1906 (the Wiley Act), which imposed standards for strength and purity and prohibited misbranding and adulteration. Its administration was in the hands of the Bureau of Chemistry, which changed its name in 1927 to the Food, Drug, and Insecticide Administration and in 1930 to the familiar Food and Drug Administration (FDA).2 It was not until 1938, following the debacle (many deaths from renal and hepatic toxicity) of Elixir Sulfanilamide, that the Federal Food, Drug, and Cosmetic Act was passed that required proof of safety before a drug could be marketed. The Kefauver-Harris Amendment in 1962 required that a drug also show premarketing proof of efficacy. From then until 1984, both generic and brand-name manufacturers were required to show proof of efficacy and safety to receive FDA marketing approval.

The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Act) greatly eased the entry of generics into the market by allowing the efficacy and safety of the original (branded) drug to apply to the generic and by only requiring the establishment of bio-equivalence for the generic.3 The Act also allowed generic drug companies to do bioequivalency testing and seek FDA approval before the expiration of the brand-name patent, thus allowing a rapid launch when the patent did expire.4

Brand-name patents
Patents were initially granted for 17 years, but this was extended to 20 years in 1995. The Hatch-Waxman Act recognized that with pharmaceuticals, the time from patent filing to FDA approval could take many years, which limited the time a company had to recoup its substantial investment and return profit to its investors. Consequently, a patent could be extended for up to 5 years to make up for time lost in the pipeline.5

Companies go to considerable lengths to protect the patents of their successful drugs, and generic drug companies go to considerable lengths to minimize the impact of such patents.6 One example was that the Act allowed 30-month stays of approval if the brand-name companies filed patent infringement suits against the generic companies. Apparently, the manufacturers of Paxil were able to extend its marketing exclusivity by 65 months by initiating several different patent disputes (the Medicare Modernization Act of 2003 restricted the stay to a single 30-month period).7

As one might imagine, having a period of generic exclusivity would allow a company to undercut the brand-name drug in price yet still reap substantial financial benefit. The Hatch-Waxman Act contained a 180-day exclusivity provision to reward the first generic company (sometimes more than one) that challenges a patent as not being valid or shows that there will be no patent infringement by its generic product. Even this absolute exclusivity can be foiled if the brand manufacturer provides a license to another generic company to manufacture its version of the drug.6 This, too, is an area of much controversy and contention.8 Once the 180 days have passed, the floodgates open and prices of generics are likely to tumble dramatically.

Generic bioequivalency
The FDA describes a generic drug as “a copy that is the same as a brand-name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use.”9 The FDA does allow differences in generics that include “shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration date. . . .”10

To show that a generic drug has therapeutic equivalence, it must be shown to be bioequivalent to the branded product. The FDA defines bioavailability as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.”10 The usual study (there can be variations) to test bio- equivalence involves a crossover design using healthy volunteers (usually 24 to 36) who receive single doses of the brand-name or generic drug.

Blood or plasma levels are measured and area under the curve (AUC), peak concentration (Cmax), and time to peak concentration (Tmax) are calculated. The statistics used to evaluate bioequivalence are a bit more complicated than the often quoted range of 80% to 125% of the reference drug. In brief, 90% confidence intervals are calculated for both AUC and Cmax, and it is these intervals that must lie entirely within the 80% to 125% range.10,11 According to the FDA, “The current practice of carrying out 2 one-sided tests at the 0.05 level of significance ensures that there is no more than a 5% chance that a generic product that is not truly equivalent to the reference will be approved.”10 One might construe this to mean that there is a 1 in 20 chance that a drug that is not truly equivalent will be approved. Many issues have been raised about this process of generic approval, including the use of normal volunteers, single-dose testing, the use of average versus individual bioequivalence, and other concerns about study design and how data are selected to be submitted to the FDA.11

Generic alternative Bioequivalent drugs may still not be deemed therapeutically equivalent if “they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety or are of different dosage forms or strengths.”9 In such cases, the term “therapeutic alternative” is used. An example of a therapeutic alternative (not AB-rated) is Osmotica’s venlafaxine extended-release tablet, which was FDA approved in May 2008 for MDD and social anxiety disorder to compete with Wyeth’s Effexor XR capsules (whose extended-release formulation continues to be patent-protected). Apparently, because it is not therapeutically equivalent, the Osmotica product cannot be substituted for Effexor XR in many states without prescriber consent.12

Quality control
Given the large number of generic manufacturers, both within the United States and abroad, the FDA faces a daunting task to ensure the quality of all generics. In September 2008, it issued a ban on the import from India of 30 generics manufactured by Ranbaxy Laboratories because of manufacturing problems at 2 plants.13 The FDA safety net is stretched thin, however, and it remains possible that some less than desirable generics could reach the consumer.

Antidepressant specifics
For every brand-name drug that goes generic, there seems to be a burst of articles (usually case reports and Internet postings) that indicate that the generic is less effective or tolerable in some patients. Within psychiatry, drugs for which concerns have been expressed include antiepileptics, anxiolytics, antipsychotics (particularly clozapine), and antidepressants.14,15

In 2001, Prozac became the first of the newer antidepressants to fall to the generic onslaught, and what initially cost dollars a day is now available for just pennies a day. A typical case report described a patient who after several years of emotional stability with Prozac relapsed into sadness 16 days after generic fluoxetine had been substituted because of insurance restrictions.16 A 6-month, double-blind, crossover study that involved 40 patients with MDD compared branded and generic fluoxetine and concluded that the crossover “did not cause any significant changes in efficacy or adverse events,” although the authors did acknowledge that the drug’s long half-life may have confounded the results.17

Another report described 20 patients in an anxiety disorders clinic who had either a worsening of anxiety symptoms or new adverse effects when they switched therapies from branded (Celexa) to generic citalopram; all these patients responded favorably when Celexa was restarted.18 The authors were careful to acknowledge limitations of the study, viewing it as informative rather than definitive. Rosenthal and colleagues19 presented the cases of 7 patients treated with citalopram or paroxetine who experienced a reemergence of symptoms after switching therapies from a brand to generic or from one generic to another generic agent.19

In 2001, the Boise VA Medical Cen­ter switched the therapies of all patients (N = 103) who were receiving twice-daily Wellbutrin SR to twice-daily generic immediate-release bu­pro­pion with substantial cost savings. A retrospective chart review revealed no seizures and minimal adverse effects.20 However, the small sample size and retrospective nature of the study greatly limit generalizations.

The plot thickens when it comes to bupropion. The growing number of reports from patients who complained of loss of effectiveness or adverse effects after switching from Wellbutrin XL 300 mg to Teva’s generic, Budeprion XL 300 mg, raised issues about the bioequivalence of the 2 preparations, which have different release mechanisms.21 Independent in vitro testing by ConsumerLab.com found that the release characteristics of the 2 preparations differed, particularly in Tmax and the amount of drug that reached the bloodstream in the first 2 and 4 hours, which suggests “dose dumping” as a possible explanation for patient complaints.22,23 These data were submitted to the FDA. On April 16, 2008, the FDA published a review of therapeutic equivalence between generic bupropion XL 300 mg and Wellbutrin XL 300 mg.24 The report mentions receipt of 85 postmarketing reports (up to June 30, 2007), 78 of which concerned loss of efficacy and others of new or worsening adverse effects after switching to bupropion XL (Teva Pharmaceuticals) 300 mg. Furthermore, the majority of those who switched back to Wellbutrin XL reported improvement. At issue was whether lack of bioequivalence accounted for these problems.

The FDA noted that its approval of both twice-daily Wellbutrin SR and once-daily Wellbutrin XL was based on bioequivalence to thrice-daily Wellbutrin IR and did not require independent proof of efficacy studies. The same held true with Budeprion XL that was approved by the FDA in 2006. Using a 150-mg dose, the bioavailability of the generic was well within the required bioequivalence limits when compared with Wellbutrin XL (Table 2). This was also true for hydroxybupropion, the active metabolite. While the issue of efficacy and tolerability was with the 300-mg tablet, the FDA stated that it was not studied because of seizure risk (odd, since Wellbutrin XL had already been approved by the FDA as a single daily dose up to 450 mg), but it did not expect a difference in pharmacokinetic profile compared with the 150-mg tablet.

Also determined, but not required for approval, was Tmax, which differed between the 2 products (Wellbutrin XL: bupropion 5 to 6 hours, hydroxybupropion 12 hours; Budeprion XL: bupropion 2 to 3 hours, hydroxybupropion 10 hours) (Figure). The FDA did not consider these differences to be clinically significant because the maximum concentrations did not differ and because the Tmax was similar to that of Wellbutrin SR and slower than that of Wellbutrin IR.

The FDA suggested that the reports of switch problems “are far more likely to be a consequence of the natural course of treated MDD than of the small pharmacokinetic differences between the generic and branded product.” Consequently, the FDA reaffirmed that it considers “the generic form of bupropion XL 300 mg bioequivalent and therapeutically equivalent to Wellbutrin XL 300 mg.”

Later that year, an article published in The Medical Letter concluded: “There is no acceptable evidence that Budeprion XL or any other generic formulation of bupropion is less effective or less safe than any corresponding formulation of Wellbutrin.”25 It also stated that absent a double-blind trial, testing the 300-mg formulations in volunteers “might be helpful.”

The saga continued into the summer of 2008, when Joe Graedon, cofounder of People’s Pharmacy, and others met with senior officials at the FDA Center for Drug Evaluation and Research.26 There was agreement that a study could be done that would compare both versions of the 300-mg XL products in patients who had experienced problems. Apparently, the FDA is designing a crossover protocol, but nothing definitive has appeared to date (J. Graedon, oral communication, January 22, 2009). Mean-while, the FDA continues to support its April 2008 decision.

Conclusions
Where does all of the brand-name versus generic brouhaha leave the clinician and the patient? One cannot conclude simply that brand-name drugs are good (and expensive) and generics are bad (and inexpensive). Had the Hatch-Waxman Act not eliminated the need for generic drug manufacturers to do the same efficacy and safety testing as branded drug manufacturers, there would be far, far fewer generics on the market (and at substantially higher prices). It is clear that when generics appear, the intensive and extensive marketing of the branded equivalent disappears as the revenue stream atrophies. Insurance programs and restrictive formularies will continue to direct clinicians toward generic prescribing. Few patients will want to bear the cost of a brand-name drug when a less expensive generic is available, especially patients with an illness such as depression that usually requires long-term treatment.

This may be an oversimplification, but it would seem reasonable for an FDA-approved generic of a brand-name drug to be preferred for patients who have not previously taken that chemical entity. Of greater potential concern are patients whose therapy is switched from a branded drug to its generic equivalent. It is difficult to estimate how much of a concern this would be. Case reports of problems, particularly those that are well substantiated because of differences in bioequivalence, are dwarfed by the number of patients who have a trouble-free transition. Of course, there are exceptions, and transition back to the original drug is quite reasonable and should be allowed in a way that does not penalize the patient financially.

Meeting FDA requirements for therapeutic equivalence should not be viewed as being synonymous with therapeutic identicalness (the same should also apply when switching among generics). In addition, it is impossible to ensure the quality of all generics at all times, so one must always remain open to the possibility of substitution mischief.

Patient education should do much to allay anxieties that otherwise might accompany an unannounced switch that could confuse a patient confronted with a pill of different size, shape, and scoring. Should problems still occur in the well-educated patient, alternative explanations for the problem should be excluded before re-prescribing the original drug.

Finally, this article does not address the far thornier issue of therapeutic substitution by which a pharmacist might replace a prescribed drug with a chemically different drug from within the same therapeutic category (eg, fluoxetine for bupropion). Very strong arguments can be made against such a practice when dealing with antidepressants (and other medications).

The prescription of a specific medication is the result of a complex decision process involving clinician and patient after careful attention to numerous factors, including efficacy, adverse effects, drug interactions, and comorbid conditions. Absent the fully informed consent of the prescriber, therapeutic substitution is a potentially dangerous practice that should be vigorously discouraged.

Drugs Mentioned in This Article
Amitriplyline (Elavil)
Bupropion (Budeprion, Wellbutrin)
Citalopram (Celexa)
Clozapine (Clozaril)
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Olanzapine and fluoxetine (Symbyax)
Paroxetine (Paxil)
Quetiapine (Seroquel)
Venlafaxine (Effexor XR)

 

References:

1. Elliott G. Basics of US patents and the patent system. AAPS J. 2007;9:E317-E324.
2. Swann JP. U.S. History of the FDA. U.S. Food and Drug Administration. http://www.fda.gov/oc/history/historyoffda/default.htm. Accessed March 11, 2009.
3. Frank RG. Regulation of follow-on biologics. N Engl J Med. 2007;357:841-843.
4. Frank RG. The ongoing regulation of generic drugs. N Engl J Med. 2007;357:1993-1996.
5. Glover GJ. The influence of market exclusivity on drug availability and medical innovations. ASPS J. 2007;9:E312-E316.
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7. Kesselheim AS. Intellectual property policy in the pharmaceutical sciences: the effect of inappropriate patents and market exclusivity extensions on the health care system. AAPS J. 2007;9:E306-E311.
8. Center for Drug Evaluation and Research. 180-Day generic drug exclusivity. U.S. Food and Drug Administration. http://www.fda.gov/CDER/about/smallbiz/generic_exclusivity.htm. Updated September 13, 2001. Accessed March 11, 2009.
9. Center for Drug Evaluation and Research. Generic drugs: questions and answers. U.S. Food and Drug Administration. http://www.fda.gov/buyonlineguide/ generics_q&a.htm. Published July 31, 2002. Accessed March 11, 2009.
10. U.S. Department of Health and Human Services. Approved drug products with therapeutic equivalence evaluations. 29th ed. 2009. http://www.fda.gov/cder/ orange/obannual.pdf. Accessed March 11, 2009.
11. Meyer MC. United Stated Food and Drug Administration requirements for approval of generic drug products. J Clin Psychiatry. 2001;62(suppl 5):4-9.
12. New venlafaxine extended-release formulation. Pharmacist’s Letter/Prescriber’s Letter. 2009;25: 250108.
13. 30 Ranbaxy generic drugs banned by FDA. NEWSInferno. September 17, 2008. http://www.newsinferno.com/archives/3838. Accessed March 11, 2009.
14. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25:1578-1592.
15. Kumet R, Gelenberg AJ. The effectiveness of generic agents in psychopharmacologic treatment. Essent Psychopharmacol. 2005;6:104-111.
16. Shields BJ, Nahata MC. Efficacy of brand-name vs. generic fluoxetine. Perspect Psychiatr Care. 2003;39:122, 135.
17. Bakish D, Miller C, Hooper CL, et al. A double-blind, crossover study comparing generic and brand fluoxetine in the treatment of major depressive disorder. Poster presented at 40th Annual Meeting of National Institute of Mental Health, New Clinical Drug Evaluation Unit (NCDEU); May 30-June 2, 2000; Boca Raton, FL.
18. Van Ameringen M, Mancini C, Patterson B, Bennett M. Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series. J Psychopharmacol. 2007;21:472-476.
19. Rosenthal J, Kong B, Jacobs L, Katzman M. Did a switch to a generic antidepressant cause relapse?
J Fam Pract. 2008;57:109-114.
20. Mayo JL, Cahill GM, Lott RS. Conversion from sustained-release to immediate-release bupropion: patient tolerability and economic impact. Pharmacotherapy. 2005;25:520-525.
21. The People’s Pharmacy With Joe and Terry Graedon. Generic antidepressant raises questions. July 16, 2007. http://www.peoplespharmacy.com/archives/print/generic_antidepressant_raises_questions.asp. Accessed March 11, 2009.
22. The People’s Pharmacy With Joe and Terry Graedon. Generic drug equality questioned. http:// www. peoplespharmacy.com/archives/generic_ drug-problems/generic_drug_equality_questioned. php?page=8. Accessed March 11, 2009.
23. Stenson J. Report questions generic antidepressant: ConsumerLab.com finds cheaper drug may not work the same as brand. October 12, 2007.
http://www.msnbc.msn.com/id/21142869. Accessed March 11, 2009.
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Evidence-Based References
Center for Drug Evaluation and Research. Review
of therapeutic equivalence: generic bupropion XL
300 mg and Wellbutrin XL 300 mg. U.S. Food and Drug Administration. http://www.fda.gov/cder/drug/infopage/bupropion/TE_review.htm. Published April 16, 2008. Accessed March 11, 2009.
U.S. Department of Health and Human Services. Approved drug products with therapeutic equivalence evaluations. 29th ed. 2009. http://www.fda.gov/cder/ orange/obannual.pdf. Accessed March 11, 2009.