Boxed Warning & Safety Information
Important Safety Information for SYMBYAX® (olanzapine and fluoxetine HCl)
Suicidality and Antidepressant drugs—Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of SYMBYAX or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SYMBYAX is not approved for use in pediatric patients.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis—Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-controlled patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure or sudden death) or infectious (eg, pneumonia) in nature. SYMBYAX is not approved for the treatment of elderly patients with dementia-related psychosis.
Clinical Worsening and Suicide Risk—All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially within the first few months of treatment and when changing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Prescriptions for SYMBYAX should be written for the smallest quantity necessary for good management and to reduce the risk of overdose. If discontinuing treatment, the medication should be tapered. It should be noted that SYMBYAX is not approved for use in treating any indications in the pediatric population.
Safety experience in elderly patients with dementia-related psychosis—In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively). Olanzapine is not approved for the treatment of patients with dementia-related psychosis.
Cerebrovascular adverse events (CVAE), including stroke, in elderly patients with dementia—Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of CVAE in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.
Hyperglycemia —Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics, including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics. Physicians should consider the risks and benefits when prescribing SYMBYAX to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose levels. Patients taking SYMBYAX should be monitored regularly for worsening of glucose control. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.
Hyperlipidemia—Undesirable alterations in lipids have been observed with SYMBYAX use. Clinical monitoring, including baseline and follow-up lipid evaluations in patients using SYMBYAX, is advised. Significant, and sometimes very high, elevations in triglyceride levels have been observed with SYMBYAX use. Significant increases in total cholesterol have also been seen with SYMBYAX use.
Weight gain—Potential consequences of weight gain should be considered prior to starting SYMBYAX. Patients receiving SYMBYAX should receive regular monitoring of weight.
Orthostatic hypotension—SYMBYAX may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period. Particular caution should be used in patients with known cardiovascular disease, cerebrovascular disease, or those predisposed to hypotension.
Allergic events and rash—In premarketing trials, the overall incidence of rash or allergic events with SYMBYAX was similar to that with placebo (4.6%, 26/571 vs 5.2%, 25/477). In fluoxetine clinical studies, 7% of 10,782 fluoxetine treated patients developed various types of rashes and/or urticaria. If rash or other possibly allergic phenomena appear for which an alternative etiology cannot be determined, immediate discontinuation is recommended.
Serotonin syndrome—Development of a potentially life-threatening serotonin syndrome may occur with SYMBYAX treatment, particularly with concomitant use of serotonergic drugs, including triptans. Concomitant use is not recommended.
Concomitant use—Caution should be used when prescribing medications that contain olanzapine or fluoxetine HCl with SYMBYAX.
Abnormal bleeding—Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of SYMBYAX with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.
Mania/hypomania—Because of the cyclical nature of bipolar disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with SYMBYAX.
Discontinuation of treatment—Symptoms associated with discontinuation of fluoxetine, a component of SYMBYAX, have been reported (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances). While these events are generally self-limiting, some have been serious. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
Prolactin—As with other drugs that antagonize dopamine receptors, SYMBYAX elevates prolactin levels, and a modest elevation persists during administration; however, possibly associated clinical manifestations were infrequently observed.
Hyponatremia—As with other antidepressants, SYMBYAX has been associated with cases of clinically significant hyponatremia that appeared to be reversible when SYMBYAX was discontinued.
Special populations and elderly—Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. In 5 olanzapine studies in elderly patients with dementia-related psychosis, adverse events observed at a greater incidence with olanzapine than with placebo were falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. Olanzapine and SYMBYAX are not approved for the treatment of patients with dementia-related psychosis. As with other CNS-active drugs, olanzapine and SYMBYAX should be used with caution in elderly patients with dementia.
Special populations, adolescents—The safety and efficacy of SYMBYAX have not been established in patients under the age of 18 years.
Transient, asymptomatic elevations of hepatic transaminase—In premarketing trials, statistically significant ALT (SGPT) elevations (>3 times the upper limit of the normal range) were observed in 6.3% (31/495) of patients exposed to SYMBYAX compared with 0.5% (2/384) of the placebo patients and 4.5% (25/560) of olanzapine-treated patients. None of these patients developed jaundice. Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period. Periodic assessment of transaminases is recommended in patients with significant hepatic disease.
As with all medications that contain an antipsychotic, the following considerations should be taken into account when prescribing SYMBYAX:
Neuroleptic malignant syndrome (NMS)—As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with olanzapine. If signs and symptoms appear, immediate discontinuation is recommended. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
Tardive dyskinesia (TD)—As with all antipsychotic medications, prescribing should be consistent with the need to minimize the risk of TD. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Seizures—Occurred infrequently in premarketing clinical trials (4/2066, 0.2%). Confounding factors may have contributed to many of these occurrences. SYMBYAX should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Such conditions may be more prevalent in patients age 65 years or older.
The most common treatment-emergent adverse event associated with SYMBYAX (vs placebo) in clinical trials was somnolence (22 vs 11%). Other common events were: weight gain (21 vs 3%), increased appetite (16 vs 4%), asthenia (15 vs 3%), peripheral edema (8 vs 1%), tremor (8 vs 3%), pharyngitis (6 vs 3%), abnormal thinking (6 vs 3%), and edema (5 vs 0%).
