Risperidone: Switching from Brand Name to Generic

To the Editor:

T he substitution of brand-name drugs by generic ones can contribute to a substantial decrease in healthcare costs. Most switches from brand name to generic are uneventful, but worsening of symptomatology and emergence of side effects have been reported in the literature (Borgheini 2003) [e.g., clozapine (Kluznik et al. 2001)]. To date, similar reports have not been published for most antipsychotics including risperidone.

Risperidone is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder in adolescents. It is also used to treat irritability, aggression, self-injury, tantrums, and mood swings in children with autism. Risperidone has been sold under the trade name Risperdal^®. After its patent expired in October 2008, 103 pharmaceutical companies are selling the generic product in 19 different countries (MICROMEDEX^® 2009). Here we discuss two cases of a clinical change following a switch from Risperdal to generic risperidone.

Case 1 is a 6-year-old Caucasian boy who was diagnosed with autism and severe intellectual disability. Since age 5, he has been treated with Risperdal 0.5 mg twice a day for aggression, hyperactivity, and irritability. He has been stable at this dose for over 6 months, until his mother reported worsening of his behavior with increase in hyperactivity and irritability. No environmental changes were reported. Interval history revealed that the patient was switched from Risperdal to generic form at 2 weeks prior to the worsening of his condition. Based on these findings, Risperdal was reinitiated. The patient progressively returned to his baseline level of functioning within 10 days. Three months later, the patient continued to be stable with limited behavioral difficulties. Six months later, his mother ran out of Risperdal and decided to rechallenge with the generic form. A few days after the substitution, worsening of the patient's clinical status was observed, which led his mother to obtain a prescription for Risperdal, leading to a progressive return of the patient to baseline.

Case 2 is a 14-year-old Asian girl who was diagnosed with paranoid schizophrenia. Since age 13, following a period of hospitalization, the patient has been on Risperdal 1 mg daily. The patient has been free of auditory hallucinations and paranoid delusions for over 9 months. During a routine follow-up appointment, the patient's mother reported an increase in tiredness and sedation for 4 weeks. No changes or stressors at school and home were identified. Clinical evaluation revealed neither worsening of psychotic features, emergence of depressive symptoms, nor any changes in the patient's functioning at school. Interval history from mother revealed that the emergence of symptoms occurred within a few days of switching from Risperdal to one of its generic forms. This finding prompted reinitiation of Risperdal. The patient's newly experienced side effects disappeared within a week. She continued to be stable on the same dose at the follow-up visit at 3 months later.

In the United States, the approval of a generic drug requires the submission of an abbreviated new drug application, which encompasses single-dose bioequivalence (BE) studies in healthy adult volunteers (vs. target patient population) (Borgheini 2003). No titration to steady state is required. No comparisons in efficacy or side effects are needed. These limitations of the requirements can potentially result in significant differences in pharmacokinetics between a brand-name and a generic product. Further, until recently, the U.S. Food and Drug Administration did not specify whether all BE studies must be submitted with the abbreviated new drug application (Shuren 2009). Generic drug companies can submit evidence of BE with passing results only and withhold evidence with nonpassing results. [Note: Effective July 15, 2009, the U.S. Food and Drug Administration requires submission of all BE data (Shuren 2009).] Thus, a switch from a brand-name to a generic drug can potentially result in either lower or higher serum drug levels, causing loss of efficacy (as in case 1) or emergence of side effects (as in case 2). In light of these observations, we recommend physicians to alert patients and their families who switch from a brand-name to a generic drug (e.g., risperidone) to be vigilant for return of symptoms or development of side effects.