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(Drug information on 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(Drug information on 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(Drug information on 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.