RxPRODUCT NEWS: PROFILE: Symbyax (Olanzapine/Fluoxetine)

Bipolar disorder affects >2 million adults in the United States. It is a brain disorder that is characterized by alternating patterns of mood swings. It usually develops in late adolescence or early childhood.¹ It is manifested as euphoria and depression, with intermittent episodes of normal mood. The flares of these episodes may last from weeks to months, causing unusual shifts in mood, energy, and ability to function and even suicidal intentions.

Treatments for bipolar disorder have included mood stabilizers and antidepressants. People with bipolar disorder are at risk of switching into mania during antidepressant treatment. Therefore, mood stabilizers such as lithium, valproic acid, and newer agents, including atypical antipsychotic medications, are required in combination with antidepressants.¹ Symbyax, a new combination product containing olanzapine and fluoxetine, is FDAapproved for the treatment of depressive episodes in patients with bipolar disorder.^2,3

Pharmacology

The exact mechanism of Symbyax is unknown. Olanzapine is a psychotropic agent that has strong affinity to serotonin 5HT_2A-2C, dopamine D_1-4, muscarinic M_1-5, histamine H₁, and adrenergic alpha-1 receptors.² Fluoxetine is a selective serotonin reuptake inhibitor. It is also a weak inhibitor of norepinephrine and dopamine transporters. Fluoxetine has low affinity for muscarinic, alpha-1 adrenergic, and histamine receptors.² It is theorized that the activation and synergistic increase in serotonin, norepinephrine, and dopamine are responsible for the antidepressant effect of Symbyax.²

Clinical Trials

Symbyax was studied in a doubleblind, international, placebo-controlled, multicenter, randomized trial. A total of 833 patients with bipolar I disorder and with their most recent episode a depressed episode?as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)⁴?were enrolled in this study. Patients were randomly assigned to received olanzapine 5 to 20 mg/day, Symbyax 6/25, 12/25, or 12/50 mg/day, or placebo for 8 weeks. The results showed that patients receiving either olanzapine or Symbyax had greater health-related quality- of-life (HRQOL) improvements, compared with those on placebo. In addition, the Symbyax group was associated with greater HRQOL improvements than the olanzapine group.⁵

Another multicenter, randomized, double-blind, parallel study was conducted to compare the efficacy and safety of Symbyax therapy and olanzapine monotherapy with placebo in the treatment of bipolar I depression. A total of 1072 patients at least 18 years of age and meeting DSM-IV criteria were recruited to participate. In all, 833 patients were enrolled, and they were randomly assigned to receive placebo (n = 337), olanzapine 5 to 20 mg/day (n = 370), or Symbyax 6/25, 6/50, or 12/50 mg/day (n = 86). The olanzapine and Symbyax groups showed greater improvement in depressive symptoms, versus the placebo group (P <.001), throughout the entire 8-week study period. The Symbyax group also showed greater improvement than the olanzapine group at weeks 4 through 8. The investigators concluded that Symbyax is more effective than olanzapine alone or placebo for the treatment of bipolar I depression, with no increased risk of manic episodes.⁶

Safety

Overall, Symbyax is well tolerated. The most common side effects are weight gain, somnolence, dry mouth, increased appetite, diarrhea, and asthenia.^2,3 Overdose with Symbyax may result in more serious complications, including arrhythmias, ataxia, coma, confusion, seizures, lethargy, and loss of consciousness. ² Contraindications include concurrent use of thioridazine, mesoridazine, monoamine oxidase inhibitors (MAOIs), and pregnancy or breast-feeding.^2,3 If MAOIs are used, therapy must be stopped 14 days prior to the initiation of Symbyax. Caution also should be used when treating patients with hepatic or renal dysfunction, hemodynamic instability, and diabetes. Additional caution is advised when using this combination product in elderly patients.² Patients taking Symbyax should avoid alcohol use and excessive exposure to sunlight, and they should drink plenty of fluids to prevent dehydration.³

Outlook

Symbyax is available as 6/25-, 6/50-, 12/25-, and 12/50-mg capsules (olanzapine/fluoxetine respectively). It is recommended that it be taken once daily in the evening.² Studies have reported that Symbyax is more effective than olanzapine or placebo for bipolar I depression, without an increased risk for manic episodes. Furthermore, trials have reported a similar Symbyax safety profile to that of its individual components. Symbyax gives health care practitioners another safe and effective option for the treatment of depressive episodes in patients with bipolar I disorder.

Drs. Faria and Soo are both senior research pharmacists with the Investigational Drug Service at Brigham and Women's Hospital, Boston, Mass. Dr. Faria also is a senior human research specialist at Partners HealthCare System. Ms. Chow is a sixthyear PharmD candidate at the Massachusetts College of Pharmacy and currently is a student in the Investigational Drug Service at Brigham and Women's Hospital.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.