Recommended Topic Related To:

Fetzima

"The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.

Major depressive disorder (MDD), commonly referred to as depression, is a mental disorder characterized by mo"...

Fetzima

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Clinical Worsening and Suicide Risk

Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (MDD) and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1: Suicidality per 1000 Patients Treated

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

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 during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for Major Depressive Disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.

Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SYMBYAX should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

It should be noted that SYMBYAX is not approved for use in treating any indications in patients less than 10 years of age [see Use in Specific Populations].

Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SYMBYAX is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING, and PATIENT INFORMATION].

In olanzapine 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).

Cerebrovascular Adverse Events (CVAE), Including Stroke

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 cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine and SYMBYAX are not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING and PATIENT INFORMATION].

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. 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.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported [see PATIENT INFORMATION].

Hyperglycemia

Adults

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 level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL). Patients taking SYMBYAX should be monitored regularly for worsening of glucose control. Patients starting treatment with SYMBYAX should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see PATIENT INFORMATION].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. 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.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, SYMBYAX was associated with a greater mean change in random glucose compared to placebo (+8.65 mg/dL vs. -3.86 mg/dL). The difference in mean changes between SYMBYAX and placebo was greater in patients with evidence of glucose dysregulation at baseline (including those patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥ 200 mg/dL, or a baseline fasting glucose level ≥ 126 mg/dL). SYMBYAX-treated patients had a greater mean HbA1c increase from baseline of 0.15% (median exposure 63 days), compared to a mean HbA1c decrease of 0.04% in fluoxetine-treated subjects (median exposure 57 days) and a mean HbA1c increase of 0.12% in olanzapine-treated patients (median exposure 56 days).

In an analysis of 6 controlled clinical studies, a larger proportion of SYMBYAX-treated subjects had glycosuria (4.4%) compared to placebo-treated subjects (1.4%).

The mean change in nonfasting glucose in patients exposed at least 48 weeks was +5.9 mg/dL (N=425).

Table 2 shows short-term and long-term changes in random glucose levels from adult SYMBYAX studies.

Table 2: Changes in Random Glucose Levels from Adult SYMBYAX Studies

  Category Change (at least once) from Baseline Treatment Arm Up to 12 weeks exposure At least 48 weeks exposure
N Patients N Patients
LaboratoryAnalyte Normal to High ( < 140 mg/dL to ≥ 200 mg/dL) Symbyax 609 2.30% 382 3.10%
Placebo 346 0.30% NAa NAa
Random Glucose Borderline to High ( ≥ 140 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) Symbyax 44 34.10% 27 37.00%
Placebo 28 3.60% NAa NAa
aNot Applicable.

Controlled fasting glucose data is limited for SYMBYAX; however, in an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (+2.76 mg/dL vs. +0.17 mg/dL).

The mean change in fasting glucose for olanzapine-treated patients exposed at least 48 weeks was +4.2 mg/dL (N=487). In analyses of patients who completed 9-12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Children and Adolescents

In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for treatment of bipolar I depression in patients 10 to 17 years of age, there were no clinically meaningful differences observed between SYMBYAX and placebo for mean change in fasting glucose levels. Table 3 shows categorical changes in fasting blood glucose from the pediatric SYMBYAX study.

Table 3: Changes in Fasting Glucose Levels from a Single Pediatric SYMBYAX Study in Bipolar Depression

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 8 weeks exposure
N Patients
Fasting Glucose Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) Symbyax 125 4.80%
Placebo 65 1.50%
Normal/IGTa to High ( < 126 mg/dL to ≥ 126 mg/dL) Symbyax 156 5.80%
Placebo 78 1.30%
Normal/IGT ( < 126 mg/dL) to ≥ 140 mg/dL) Symbyax 156 1.90%
Placebo 78 0.00%
aImpaired Glucose Tolerance.

Olanzapine Monotherapy in Adolescents

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with Schizophrenia (6 weeks) or Bipolar I Disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (+2.68 mg/dL vs -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was +3.1 mg/dL (N=121). Table 4 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 4: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 12 weeks exposure At least 24 weeks exposure
N Patients N Patients
       
Fasting Glucose Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) Olanzapine 124 0% 108 0.90%
Placebo 53 1.90% NAa NAa
Borderline to High ( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Olanzapine 14 14.30% 13 23.10%
Placebo 13 0% NAa NAa
aNot Applicable.

Hyperlipidemia

Undesirable alterations in lipids have been observed with SYMBYAX use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using SYMBYAX, is recommended [see PATIENT INFORMATION].

Adults

Clinically meaningful, and sometimes very high ( > 500 mg/dL), elevations in triglyceride levels have been observed with SYMBYAX use. Clinically meaningful increases in total cholesterol have also been seen with SYMBYAX use.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, SYMBYAX-treated patients had an increase from baseline in mean random total cholesterol of 12.1 mg/dL compared to an increase from baseline in mean random total cholesterol of 4.8 mg/dL for olanzapine-treated patients and a decrease in mean random total cholesterol of 5.5 mg/dL for placebo-treated patients. Table 5 shows categorical changes in nonfasting lipid values.

In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), changes (at least once) in nonfasting total cholesterol from normal at baseline to high occurred in 12% (N=150) and changes from borderline to high occurred in 56.6% (N=143) of patients. The mean change in nonfasting total cholesterol was 11.3 mg/dL (N=426).

Table 5: Changes in Nonfasting Lipids Values from Controlled Clinical Studies with Treatment Duration up to 12 Weeks

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm N Patients
Nonfasting Triglycerides Increase by ≥ 50 mg/dL OFC 174 67.80%
Olanzapine 172 72.70%
Normal to High ( < 150 mg/dL to ≥ 500 mg/dL) OFC 57 0%
Olanzapine 58 0%
Borderline to High ( ≥ 150 mg/dL and < 500 mg/dL to ≥ 500 mg/dL) OFC 106 15.10%
Olanzapine 103 8.70%
Nonfasting Total Cholesterol Increase by ≥ 40 mg/dL OFC 685 35%
Olanzapine 749 22.70%
Placebo 390 9%
Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) OFC 256 8.20%
Olanzapine 279 2.90%
Placebo 175 1.70%
Borderline to High ( ≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL) OFC 213 36.20%
Olanzapine 261 27.60%
Placebo 111 9.90%

Fasting lipid data is limited for SYMBYAX; however, in an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, patients with high baseline lipid levels.

In long-term olanzapine studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4-6 months.

The proportion of olanzapine-treated patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 6 shows categorical changes in fasting lipids values.

Table 6: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 12 weeks exposure At least 48 weeks exposure
N Patients N Patients
Fasting Triglycerides Increase by ≥ 50 mg/dL Olanzapine 745 39.60% 487 61.40%
Placebo 402 26.10% NAa NAa
Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) Olanzapine 457 9.20% 293 32.40%
Placebo 251 4.40% NAa NAa
Borderline to High ( ≥ 150 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) Olanzapine 135 39.30% 75 70.70%
Placebo 65 20.00% NAa NAa
Fasting Total Cholesterol Increase by ≥ 40 mg/dL Olanzapine 745 21.60% 489 32.90%
Placebo 402 9.50% NAa NAa
Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) Olanzapine 392 2.80% 283 14.80%
Placebo 207 2.40% NAa NAa
Borderline to High ( ≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL) Olanzapine 222 23.00% 125 55.20%
Placebo 112 12.50% NAa NAa
Fasting LDL Cholesterol Increase by ≥ 30 mg/dL Olanzapine 536 23.70% 483 39.80%
Placebo 304 14.10% NAa NAa
Normal to High ( < 100 mg/dL to ≥ 160 mg/dL) Olanzapine 154 0% 123 7.30%
Placebo 82 1.20% NAa NAa
Borderline to High ( ≥ 100 mg/dL and < 160 mg/dL to ≥ 160 mg/dL) Olanzapine 302 10.60% 284 31.00%
Placebo 173 8.10% NAa NAa
aNot Applicable.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the median increase in total cholesterol was 9.4 mg/dL.

Children and Adolescents

In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for treatment of bipolar I depression in patients 10 to 17 years of age, there were clinically meaningful and statistically significant differences observed between SYMBYAX and placebo for mean change in fasting total cholesterol (+16.3 mg/dL vs. -4.3 mg/dL, respectively), LDL cholesterol (+9.7 mg/dL vs -3.5 mg/dL, respectively), and triglycerides (+35.4 mg/dL vs. -3.5 mg/dL, respectively).

The magnitude and frequency of changes in lipids were greater in children and adolescents than previously observed in adults. Table 7 shows categorical changes in fasting lipids values from the pediatric SYMBYAX study.

Table 7: Changes in Fasting Lipids Values from a Single Pediatric SYMBYAX Study in Bipolar Depression

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 8 weeks exposure
N Patients
Fasting Triglycerides Increase by ≥ 50 mg/dL OFC 158 70.30%
Placebo 81 38.30%
Normal to High ( < 90 mg/dL to ≥ 130 mg/dL) OFC 71 39.40%
Placebo 31 19.40%
Borderline to High ( ≥ 90 mg/dL and < 130 mg/dL to ≥ 130 mg/dL) OFC 13 84.60%
Placebo 12 33.30%
Normal/borderline to High ( < 130 mg/dL to ≥ 130 mg/dL) OFC 106 52.80%
Placebo 56 25.00%
Normal to borderline/high ( < 90 mg/dL to ≥ 90 mg/dL) OFC 71 73.20%
Placebo 31 41.90%
Normal/borderline/high to very high ( < 500 mg/dL to ≥ 500 mg/dL) OFC 158 2.50%
Placebo 81 1.20%
Fasting Total Cholesterol Increase by ≥ 40 mg/dL OFC 158 52.50%
Placebo 81 8.60%
Normal to High ( < 170 mg/dL to ≥ 200 mg/dL) OFC 81 12.30%
Placebo 44 4.50%
Borderline to High ( ≥ 170 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) OFC 22 72.70%
Placebo 11 24.30%
Normal/borderline to High ( < 200 mg/dL to ≥ 200 mg/dL) OFC 126 32.50%
Placebo 67 10.40%
Normal to borderline/high ( < 170 mg/dL to ≥ 170 mg/dL) OFC 81 58.00%
Placebo 44 31.80%
Fasting LDL Cholesterol Increase by ≥ 30 mg/dL OFC 158 53.80%
Placebo 81 23.50%
Normal to High ( < 110 mg/dL to ≥ 130 mg/dL) OFC 112 13.40%
Placebo 62 6.50%
Borderline to High ( ≥ 110 mg/dL and < 130 mg/dL to ≥ 130 mg/dL) OFC 12 75.00%
Placebo 3 0.00%
Normal/borderline to High ( < 130 mg/dL to ≥ 130 mg/dL) OFC 138 21.70%
Placebo 77 7.80%
Normal to borderline/high ( < 110 mg/dL to ≥ 110 mg/dL) OFC 112 30.40%
Placebo 62 14.50%

Olanzapine Monotherapy in Adolescents

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with Schizophrenia (6 weeks) or Bipolar I Disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term olanzapine studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 8 shows categorical changes in fasting lipids values in adolescents.

Table 8: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

Laboratory Analyte Category Change (at least once) from Baseline Treatment Arm Up to 6 weeks exposure At least 24 weeks exposure
N Patients N Patients
Fasting Triglycerides Increase by ≥ 50 mg/dL Olanzapine 138 37.00% 122 45.90%
Placebo 66 15.20% NAa NAa
Normal to High ( < 90 mg/dL to > 130 mg/dL) Olanzapine 67 26.90% 66 36.40%
Placebo 28 10.70% NAa NAa
Borderline to High ( ≥ 90 mg/dL and ≥ 130 mg/dL to > 130 mg/dL) Olanzapine 37 59.50% 31 64.50%
Placebo 17 35.30% NAa NAa
Fasting Total Cholesterol Increase by ≥ 40 mg/dL Olanzapine 138 14.50% 122 14.80%
Placebo 66 4.50% NAa NAa
Normal to High ( < 170 mg/dL to ≥ 200 mg/dL) Olanzapine 87 6.90% 78 7.70%
Placebo 43 2.30% NAa NAa
Borderline to High ( ≥ 170 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) Olanzapine 36 38.90% 33 57.60%
Placebo 13 7.70% NAa NAa
Fasting LDL Cholesterol Increase by ≥ 30 mg/dL Olanzapine 137 17.50% 121 22.30%
Placebo 63 11.10% NAa NAa
Normal to High ( < 110 mg/dL to ≥ 130 mg/dL) Olanzapine 98 5.10% 92 10.90%
Placebo 44 4.50% NAa NAa
Borderline to High ( ≥ 110 mg/dL and < 130 mg/dL to ≥ 130 mg/dL) Olanzapine 29 48.30% 21 47.60%
Placebo 9 0% NAa NAa
aNot Applicable.

Weight Gain

Potential consequences of weight gain should be considered prior to starting SYMBYAX. Patients receiving SYMBYAX should receive regular monitoring of weight [see PATIENT INFORMATION].

Adults

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, the mean weight increase for SYMBYAX-treated patients was greater than placebo-treated patients [4 kg (8.8 lb) vs -0.3 kg (-0.7 lb)]. Twenty-two percent of SYMBYAX-treated patients gained at least 7% of their baseline weight, with a median exposure to event of 6 weeks. This was greater than in placebo-treated patients (1.8%). Approximately 3% of SYMBYAX-treated patients gained at least 15% of their baseline weight, with a median exposure to event of 8 weeks. This was greater than in placebo-treated patients (0%). Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 2.5% of SYMBYAX-treated patients and 0% of placebo-treated patients.

In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), the mean weight gain was 6.7 kg (14.7 lb) (median exposure of 448 days, N=431). The percentages of patients who gained at least 7%, 15% or 25% of their baseline body weight with long-term exposure were 66%, 33%, and 10%, respectively. Discontinuation due to weight gain occurred in 1.2% of patients treated with olanzapine and fluoxetine in combination following at least 48 weeks of exposure.

In long-term olanzapine studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 9 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 9: Weight Gain with Olanzapine Use in Adults

Amount Gained kg (lb) 6 Weeks
(N=7465)
(%)
6 Months
(N=4162)
(%)
12 Months
(N=1345)
(%)
24 Months
(N=474)
(%)
36 Months
(N=147)
(%)
≤ 0 26.2 24.3 20.8 23.2 17
0 to ≤ 5 (0-11 lb) 57 36 26 23.4 25.2
> 5 to ≤ 10 (11-22 lb) 14.9 24.6 24.2 24.1 18.4
> 10 to ≤ 15 (22-33 lb) 1.8 10.9 14.9 11.4 17
> 15 to ≤ 20 (33-44 lb) 0.1 3.1 8.6 9.3 11.6
> 20 to ≤ 25 (44-55 lb) 0 0.9 3.3 5.1 4.1
> 25 to ≤ 30 (55-66 lb) 0 0.2 1.4 2.3 4.8
> 30 ( > 66 lb) 0 0.1 0.8 1.2 2

Children and Adolescents

In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for the treatment of bipolar I depression in patients 10 to 17 years of age, SYMBYAX was associated with greater mean change in weight compared to placebo (+4.4 kg vs +0.5 kg, respectively). The percentages of children and adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with 8-week exposure were 52%, 14%, and 1%, respectively. The proportion of patients who had clinically significant weight gain was greater in children and adolescent patients compared to short-term data in adults. Discontinuation due to weight gain occurred in 2.9% of SYMBYAX-treated patients and 0% of placebo-treated patients. Table 10 depicts weight gain observed in the pediatric SYMBYAX study.

Table 10: Weight Gain with OFC Use Seen in a Single Pediatric SYMBYAX Study in Bipolar Depression

Amount Gained kg (lb) Up to 8 Weeks (N=170) (%)
≤ 0 7.1
0 to ≤ 5 (0-11 lb) 54.7
> 5 to ≤ 10 (11-22 lb) 31.2
> 10 to ≤ 15 (22-33 lb) 7.1
> 15 to ≤ 20 (33-44 lb) 0
> 20 to ≤ 25 (44-55 lb) 0
> 25 to ≤ 30 (55-66 lb) 0
> 30 ( > 66 lb) 0

Olanzapine Monotherapy in Adolescents

Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

Table 11: Weight Gain with Olanzapine Use in Adolescents from 4 Placebo-Controlled Trials

  Olanzapine-treated patients Placebo-treated patients
Mean change in body weight from baseline (median exposure = 3 weeks) 4.6 kg (10.1 lb) 0.3 kg (0.7 lb)
Percentage of patients who gained at least 7% of baseline body weight 40.6% (median exposure to 7% = 4 weeks) 9.8% (median exposure to 7% = 8 weeks)
Percentage of patients who gained at least 15% of baseline body weight 7.1% (median exposure to 15% = 19 weeks) 2.7% (median exposure to 15% = 8 weeks)

In long-term olanzapine studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb) (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 12 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

Table 12: Weight Gain with Olanzapine Use in Adolescents

Amount Gained kg (lb) 6 Weeks
(N=243)
(%)
6 Months
(N=191)
(%)
≤ 0 2.9 2.1
0 to ≤ 5 (0-11 lb) 47.3 24.6
> 5 to ≤ 10 (11-22 lb) 42.4 26.7
> 10 to ≤ 15 (22-33 lb) 5.8 22
> 15 to ≤ 20 (33-44 lb) 0.8 12.6
> 20 to ≤ 25 (44-55 lb) 0.8 9.4
> 25 to ≤ 30 (55-66 lb) 0 2.1
> 30 to ≤ 35 (66-77 lb) 0 0
> 35 to ≤ 40 (77-88 lb) 0 0
> 40 ( > 88 lb) 0 0.5

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including SYMBYAX, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of SYMBYAX with MAOIs intended to treat psychiatric disorders is contraindicated. SYMBYAX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking SYMBYAX. SYMBYAX should be discontinued before initiating treatment with the MAOI [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].

If concomitant use of SYMBYAX with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with SYMBYAX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Allergic Reactions and Rash

In SYMBYAX premarketing controlled clinical studies, the overall incidence of rash or allergic reactions in SYMBYAX-treated patients [4.6% (26/571)] was similar to that of placebo [5.2% (25/477)]. The majority of the cases of rash and/or urticaria were mild; however, 3 patients discontinued (1 due to rash, which was moderate in severity and 2 due to allergic reactions, 1 of which included face edema).

In fluoxetine US clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical studies, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

In fluoxetine premarketing clinical studies, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but 1 was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.

Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, and urticaria alone and in combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possible allergic phenomena for which an alternative etiology cannot be identified, SYMBYAX should be discontinued.

Activation of Mania/Hypomania

A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that SYMBYAX is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder.

In the 3 controlled bipolar depression studies (2 in adults and 1 in children and adolescents [10 to 17 years of age]) there was no statistically significant difference in the incidence of manic reactions (manic reaction or manic depressive reaction) between SYMBYAX- and placebo-treated patients. In 1 adult study, the incidence of manic reactions was (7% [3/43]) in SYMBYAX-treated patients compared to (3% [5/184]) in placebo-treated patients. In the other adult study, the incidence of manic reactions was (2% [1/43]) in SYMBYAX-treated patients compared to (8% [15/193]) in placebo-treated patients. In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for the treatment of bipolar I depression in patients 10 to 17 years of age, the incidence of manic reactions was (1% [2/170]) in SYMBYAX- treated patients compared to (0% [0/84]) in placebo-treated patients. Because of the cyclical nature of Bipolar I Disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with SYMBYAX.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

The incidence of dyskinetic movement in SYMBYAX-treated patients was infrequent. The mean score on the Abnormal Involuntary Movement Scale (AIMS) in the SYMBYAX-controlled database across clinical studies involving SYMBYAX-treated patients decreased from baseline. Nonetheless, SYMBYAX should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on SYMBYAX, drug discontinuation should be considered. However, some patients may require treatment with SYMBYAX despite the presence of the syndrome. The need for continued treatment should be reassessed periodically.

Orthostatic Hypotension

SYMBYAX may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period [see PATIENT INFORMATION].

In the SYMBYAX-controlled clinical trials across all indications, there were no significant differences between SYMBYAX-treated patients and olanzapine, fluoxetine- or placebo-treated patients in exposure-adjusted rates of orthostatic systolic blood pressure decreases of at least 30 mm Hg. Orthostatic systolic blood pressure decreases of at least 30 mm Hg occurred in 4.0% (28/705), 2.3% (19/831), 4.5% (18/399), and 1.8% (8/442) of the SYMBYAX, olanzapine, fluoxetine, and placebo groups, respectively. In this group of studies, the incidence of syncope-related adverse reactions (i.e., syncope and/or loss of consciousness) in SYMBYAX-treated patients was 0.4% (3/771) compared to placebo 0.2% (1/477).

In a clinical pharmacology study of SYMBYAX, 3 healthy subjects were discontinued from the trial after experiencing severe, but self-limited, hypotension and bradycardia that occurred 2 to 9 hours following a single 12 mg/50 mg dose of SYMBYAX. Reactions consisting of this combination of hypotension and bradycardia (and also accompanied by sinus pause) have been observed in at least 3 other healthy subjects treated with various formulations of olanzapine (1 oral, 2 intramuscular). In controlled clinical studies, the incidence of patients with a ≥ 20 bpm decrease in orthostatic pulse concomitantly with a ≥ 20 mm Hg decrease in orthostatic systolic blood pressure was 0.3% (2/706) in the SYMBYAX group, 0.2% (1/445) in the placebo group, 0.7% (6/837) in the olanzapine group, and 0% (0/404) in the fluoxetine group.

SYMBYAX should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

Leukopenia, Neutropenia, and Agranulocytosis

Class Effect

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including SYMBYAX. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of SYMBYAX should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm³ ) should discontinue SYMBYAX and have their WBC followed until recovery.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. SYMBYAX is not approved for the treatment of patients with Alzheimer's disease.

Seizures

Seizures occurred in 0.2% (4/2547) of SYMBYAX-treated patients during open-label clinical studies. No seizures occurred in the controlled SYMBYAX studies. Seizures have also been reported with both olanzapine and fluoxetine monotherapy. SYMBYAX should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. SYMBYAX is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of ≥ 65 years of age.

Abnormal Bleeding

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of SYMBYAX and NSAIDs, aspirin, or other drugs that affect coagulation [see DRUG INTERACTIONS and PATIENT INFORMATION].

Hyponatremia

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine and SYMBYAX. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when [see Use in Specific Populations]. SYMBYAX was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of SYMBYAX should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see PATIENT INFORMATION].

Potential for Cognitive and Motor Impairment

SYMBYAX has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SYMBYAX therapy does not affect them adversely [see PATIENT INFORMATION].

Adults

Sedation-related adverse reactions were commonly reported with SYMBYAX treatment occurring at an incidence of 26.6% in SYMBYAX-treated patients compared with 10.9% in placebo-treated patients. Sedation-related adverse reactions (sedation, somnolence, hypersomnia, and lethargy) led to discontinuation in 2% (15/771) of patients in the controlled clinical studies.

Children and Adolescents

In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for the treatment of bipolar I depression in patients 10 to 17 years of age, somnolence-related adverse events were commonly reported with SYMBYAX treatment occurring at an incidence of 23.5% in SYMBYAX-treated patients compared with 2.4% in placebo-treated patients. Somnolence-related adverse events led to discontinuation in 1.2% (2/170) of patients.

Body Temperature Dysregulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing SYMBYAX for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see PATIENT INFORMATION].

QT Prolongation

Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with fluoxetine. SYMBYAX should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see CONTRAINDICATIONS, ADVERSE REACTIONS, DRUG INTERACTIONS, OVERDOSE, and CLINICAL PHARMACOLOGY].

Pimozide and thioridazine are contraindicated for use with SYMBYAX. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,; specific antibiotics (e.g.,erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Consider ECG assessment and periodic ECG monitoring if initiating treatment with SYMBYAX in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing SYMBYAX and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for the treatment of bipolar I depression in patients 10 to 17 years of age, there was a statistically significant difference in QTc interval for patients treated with SYMBYAX compared with patients on placebo: mean change in QTcF (Fridericia correction factor) from baseline to endpoint in patients treated with SYMBYAX was 8.2 msec (95% CI 6.2, 10.2). No patient developed QTc increases ≥ 60 msec or QTc ≥ 480 msec. Clinicians should use SYMBYAX with caution in those children or adolescents who are known to be particularly at risk for QT prolongation [see ADVERSE REACTIONS].

Use in Patients with Concomitant Illness

Clinical experience with SYMBYAX in patients with concomitant systemic illnesses is limited [see CLINICAL PHARMACOLOGY]. The following precautions for the individual components may be applicable to SYMBYAX.

Anticholinergic Adverse Reactions

Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical studies, SYMBYAX was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for study discontinuations; SYMBYAX should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, a history of paralytic ileus, or related conditions.

Elderly Patients with Dementia-related Psychosis

In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING, and PATIENT INFORMATION].

As with other CNS-active drugs, SYMBYAX should be used with caution in elderly patients with dementia. SYMBYAX is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised [see BOXED WARNING and PATIENT INFORMATION].

SYMBYAX has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the premarket testing.

Patients with Cardiovascular Disease

Caution is advised when using SYMBYAX in cardiac patients and in patients with diseases or conditions that could affect hemodynamic responses.

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, SYMBYAX elevates prolactin levels, and the elevation persists during administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds that increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

Adults

In controlled clinical studies of SYMBYAX (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 28% of adults treated with SYMBYAX as compared to 5% of placebo-treated patients. The elevations persisted throughout administration of SYMBYAX. In a pooled analysis from clinical studies including 2929 adults treated with SYMBYAX, potentially associated clinical manifestations included menstrual-related events1 (1% [20/1946] of females), sexual function-related events2 (7% [192/2929] of females and males), and breast-related events3 (0.8% [16/1946] of females, 0.2% [2/983] of males).

Children and Adolescents

In a single, 8-week, randomized, placebo-controlled clinical trial investigating SYMBYAX for the treatment of bipolar I depression in patients 10 to 17 years of age, SYMBYAX was associated with a statistically significant greater mean change from baseline in prolactin levels compared to placebo (8.7 mcg/L vs 0.7 mcg/L, respectively). Although prolactin concentrations were very commonly ( > 10%) elevated above normal in both the SYMBYAX and placebo groups, more than twice as many SYMBYAX-treated patients were seen with these elevations compared to placebo-treated patients. Five patients experienced an adverse event potentially associated with elevated prolactin; these events included dysmenorrhoea, galactorrhoea, and ovulation disorder.

The magnitude and frequency of change in prolactin in children and adolescents was larger than observed in adult patients treated with SYMBYAX, but was similar to that observed in adolescents treated with olanzapine monotherapy.

Olanzapine monotherapy

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (2% [49/3240] of females), sexual function-related events2 (2% [150/8136] of females and males), and breast-related events3 (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events1 (1% [2/168] of females), sexual function-related events2 (0.7% [3/454] of females and males), and breast-related events3 (2% [3/168] of females, 2% [7/286] of males), [see Use In Specific Populations].

Concomitant Use of Olanzapine and Fluoxetine Products

SYMBYAX contains the same active ingredients that are in Zyprexa®, Zyprexa® Zydis®, Zyprexa ® Relprevv™ (olanzapine), and in Prozac®, Prozac® Weekly™, and Sarafem® (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with SYMBYAX [see OVERDOSAGE].

Long Elimination Half-Life of Fluoxetine

Because of the long elimination half-lives of fluoxetine and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see CLINICAL PHARMACOLOGY].

Discontinuation Adverse Reactions

During marketing of fluoxetine, a component of SYMBYAX, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].

Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see PATIENT INFORMATION].

REFERENCES

1Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

2Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

3Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

Patient Counseling Information

See FDA-approved Medication Guide.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SYMBYAX.

Information on Medication Guide

Prescribers or other health professionals should inform patients, their families, and their caregivers about the potential benefits and potential risks associated with treatment with SYMBYAX and should counsel them in its appropriate use. A patient Medication Guide is available for SYMBYAX. The prescribers or other health professionals should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke

Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with olanzapine had a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) compared with placebo. SYMBYAX is not approved for elderly patients with dementia-related psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome (NMS)

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine, a component of SYMBYAX. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS].

Hyperglycemia

Patients should be advised of the potential risk of hyperglycemia-related adverse reactions. Patients should be monitored regularly for worsening of glucose control. Patients and caregivers should be counseled that metabolic changes have occurred during treatment with SYMBYAX. Patients who have diabetes should follow their doctor's instructions about how often to check their blood sugar while taking SYMBYAX [see WARNINGS AND PRECAUTIONS].

Hyperlipidemia

Patients should be counseled that hyperlipidemia has occurred during treatment with SYMBYAX. Patients should have their lipid profile monitored regularly [see WARNINGS AND PRECAUTIONS].

Weight Gain

Patients should be counseled that weight gain has occurred during treatment with SYMBYAX. Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS].

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SYMBYAX and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS]. Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Allergic Reactions and Rash

Patients should be advised to notify their physician if they develop a rash or hives [see WARNINGS AND PRECAUTIONS]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Patients should be advised to change positions carefully to help prevent orthostatic hypotension, and to lie down if they feel dizzy or faint, until they feel better. Patients should be advised to call their doctor if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.

Abnormal Bleeding

Patients should be cautioned about the concomitant use of SYMBYAX and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see WARNINGS AND PRECAUTIONS]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking Symbyax.

Hyponatremia

Patients should be advised that hyponatremia has been reported during treatment with SNRIs and SSRIs, including SYMBYAX. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see WARNINGS AND PRECAUTIONS].

Potential for Cognitive and Motor Impairment

SYMBYAX has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SYMBYAX therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Body Temperature Dysregulation

Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Patients should be advised to call their doctor right away if they become severely ill and have some or all of these symptoms of dehydration: sweating too much or not at all, dry mouth, feeling very hot, feeling thirsty, not able to produce urine [see WARNINGS AND PRECAUTIONS].

Concomitant Medication

Patients should be advised to inform their physician if they are taking Prozac, Prozac Weekly, Sarafem, fluoxetine, Zyprexa, Zyprexa Zydis, or Zyprexa Relprevv. Patients should be advised to inform their physicians if they are taking, plan to take, or have stopped taking any prescription or over-the-counter drugs, including herbal supplements, since there is a potential for interactions. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while taking SYMBYAX, as stopping a medication may also impact the overall blood level of SYMBYAX [see WARNINGS AND PRECAUTIONS].

Discontinuation of Treatment with SYMBYAX

Patients should be advised to take SYMBYAX exactly as prescribed, and to continue taking SYMBYAX as prescribed even after their mood symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking SYMBYAX, without consulting their physician [see WARNINGS AND PRECAUTIONS].

Alcohol

Patients should be advised to avoid alcohol while taking SYMBYAX [see DRUG INTERACTIONS].

Use In Specific Populations

Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during SYMBYAX therapy. SYMBYAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations].

Nursing Mothers - Patients, if taking SYMBYAX, should be advised not to breast-feed [see Use in Specific Populations].

Pediatric Use - Safety and efficacy of SYMBYAX in patients 10 to 17 years of age have been established for the acute treatment of Depressive Episodes Associated with Bipolar I Disorder. The types of adverse reactions observed with SYMBYAX in children and adolescents were generally similar to those observed in adults. However, the magnitude and frequency of some changes were greater in children and adolescents than adults. These included increases in lipids, hepatic enzymes, and prolactin, as well as increases in the QT interval. Educate patients, families, and caregivers about these risks [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and Use In Specific Populations].

The frequency of weight gain ≥ 7%, and the magnitude and frequency of increases in lipids, hepatic analytes, and prolactin in children and adolescents treated with SYMBYAX were similar to those observed in adolescents treated with olanzapine monotherapy [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and Use In Specific Populations].

The safety and effectiveness of Symbyax for the treatment of bipolar I depression in patients under 10 years of age have not been established. The safety and effectiveness of Symbyax for treatment resistant depression in patients under 18 years of age have not been established.

QT Prolongation

Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies were conducted with SYMBYAX. The following data are based on findings in studies performed with the individual components, therefore all dose multiples (based on body surface area) reflect the maximum recommended human dose (MRHD) of 20 mg olanzapine, or 80 mg fluoxetine, when each drug is administered separately.

Carcinogenesis

Olanzapine Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, and 30/20 mg/kg/day [equivalent to 0.8 to 5 times the maximum recommended human daily dose (MRHD) on a mg/m² basis] and 0.25, 2, and 8 mg/kg/day (equivalent to 0.06 to 2 times the MRHD on a mg/m² basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, and 4 mg/kg/day (males) and 0.25, 1, 4, and 8 mg/kg/day (females) (equivalent to 0.1 to 2 and 0.1 to 4 times the MRHD on a mg/m² basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in females dosed at 8 mg/kg/day (2 times the MRHD on a mg/m² basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2 to 5 times the MRHD on a mg/m² basis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥ 2 mg/kg/day and in female rats dosed at ≥ 4 mg/kg/day (0.5 and 2 times the MRHD on a mg/m² basis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the finding of prolactin-mediated endocrine tumors in rodents is unknown [see WARNINGS AND PRECAUTIONS ].

Fluoxetine The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the MRHD on a mg/m² basis), produced no evidence of carcinogenicity.

Mutagenesis

Olanzapine No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.

Fluoxetine Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Impairment of Fertility

Symbyax Fertility studies were not conducted with SYMBYAX. However, in a repeat-dose rat toxicology study of 3 months duration, ovary weight was decreased in females treated with the low-dose [2 and 4 mg/kg/day (1 and 0.5 times the MRHD on a mg/m² basis), respectively] and high-dose [4 and 8 mg/kg/day (2 and 1 times the MRHD on a mg/m² basis), respectively] combinations of olanzapine and fluoxetine. Decreased ovary weight, and corpora luteal depletion and uterine atrophy were observed to a greater extent in the females receiving the high-dose combination than in females receiving either olanzapine or fluoxetine alone. In a 3-month repeat-dose dog toxicology study, reduced epididymal sperm and reduced testicular and prostate weights were observed with the high-dose combination of olanzapine and fluoxetine [5 and 5 mg/kg/day (9 and 2 times the MRHD on a mg/m² basis), respectively] and with olanzapine alone (5 mg/kg/day or 9 times the MRHD on a mg/m² basis).

Olanzapine In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the MRHD on a mg/m² basis, respectively). Discontinuance of olanzapine treatment reversed the effects on male-mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the MRHD on a mg/m² basis). Diestrous was prolonged and estrous was delayed at 1.1 mg/kg/day (0.6 times the MRHD on a mg/m² basis); therefore, olanzapine may produce a delay in ovulation.

Fluoxetine Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m² basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine at a high dose (30 mg/kg) associated with significant toxicity [see Use in Specific Populations].

Use In Specific Populations

Pregnancy - Pregnancy Category C

Risk Summary

There are no adequate and well-controlled clinical studies with SYMBYAX or its components (olanzapine and fluoxetine) in pregnant women.

A number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results.

Neonates exposed to fluoxetine, a component of SYMBYAX, and other SSRIs and SNRIs late in the third trimester have developed complications arising immediately upon delivery (respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying) requiring prolonged hospitalization, respiratory support, and tube feeding. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture is consistent with serotonin syndrome. Neonates exposed to olanzapine, a component of SYMBYAX, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).

SYMBYAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, taking into account the risk of untreated Bipolar I Depression or Treatment Resistant Depression.

Human Data

There are no adequate and well-controlled clinical studies with SYMBYAX, olanzapine or fluoxetine in pregnant women. Seven pregnancies were observed during premarketing clinical studies with olanzapine, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established.

Neonates exposed to fluoxetine, a component of SYMBYAX, and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1–2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI (including fluoxetine) use in pregnancy and PPHN. Other studies do not show a significant statistical association.

Neonates exposed to antipsychotic drugs (including olanzapine, a component of SYMBYAX), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with SYMBYAX, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [see DOSAGE AND ADMINISTRATION].

SYMBYAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

Symbyax Embryo fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low-dose) [1 and 0.5 times the maximum recommended human dose (MRHD) for olanzapine (20 mg) and fluoxetine (80 mg), respectively on a mg/m² body surface area], and 4 and 8 mg/kg/day (high-dose) [2 and 1 times the MRHD on a mg/m² body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [4 and 1 times the MRHD on a mg/m² basis, respectively], and 8 and 8 mg/kg/day (high-dose) [9 and 2 times the MRHD on a mg/m² basis, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high-doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination.

In a pre- and postnatal study conducted in rats, olanzapine and fluoxetine were orally administered during pregnancy and throughout lactation in combination at dose levels up to 2 (olanzapine) plus 4 (fluoxetine) mg/kg/day (1 and 0.5 times the MRHD on a mg/m² body surface area. An elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced bodyweight (approximately 8% in female) occurred among offspring at the highest dose: the no-effect dose was 0.5 (olanzapine) plus 1 (fluoxetine) mg/kg/day (0.25 and 0.13 times the MRHD on a mg/m² body surface area). Among the surviving progeny, there were no adverse effects on physical or neurobehavioral development and reproductive performance at any dose.

Olanzapine In oral embryo-fetal studies in rats and rabbits, there was no evidence of teratogenicity following administration of olanzapine at doses up to 18 and 30 mg/kg/day, respectively (9 and 30 times the MRHD on a mg/m² basis, respectively). In a rat teratology study, early resorptions and increased numbers of dead fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD on a mg/m² basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the MRHD on a mg/m² basis). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Placental transfer of olanzapine occurs in rat pups.

Fluoxetine In oral embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg/day on a mg/mē basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/mē basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/mē basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/mē basis).

Labor and Delivery

Symbyax The effect of SYMBYAX on labor and delivery in humans is unknown. Parturition in rats was not affected by SYMBYAX. SYMBYAX should be used during labor and delivery only if the potential benefit justifies the potential risk.

Olanzapine The effect of olanzapine on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine.

Fluoxetine The effect of fluoxetine on labor and delivery in humans is unknown. Fluoxetine crosses the placenta; therefore, there is a possibility that fluoxetine may be associated with adverse effects on the newborn.

Nursing Mothers

Symbyax Studies evaluating the individual components of SYMBYAX (olanzapine and fluoxetine) in nursing mothers are described below. Because of the potential for serious adverse reactions in nursing infants from SYMBYAX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women not breast-feed when receiving SYMBYAX.

Olanzapine In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady state was estimated to be 1.8% of the maternal olanzapine dose. It is recommended that women receiving olanzapine should not breast-feed.

Fluoxetine Fluoxetine is excreted in human breast milk. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208/mL of norfluoxetine on the 2nd day of feeding.

Pediatric Use

Symbyax The safety and efficacy of SYMBYAX in patients 10 to 17 years of age has been established for the acute treatment of Depressive Episodes Associated with Bipolar I Disorder in a single 8-week randomized, placebo-controlled clinical trial (N = 255) [see Clinical Studies]. Patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. After Week 2, there was flexible dosing of SYMBYAX in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. The average dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. The recommended starting dose for children and adolescents is 3/25 mg per day (lower than that for adults). Flexible dosing is recommended, rather than the forced titration used in the study [see DOSAGE AND ADMINISTRATION].

The types of adverse events observed with SYMBYAX in children and adolescents were generally similar to those observed in adults. However, the magnitude and frequency of some changes were greater in children and adolescents than adults. These included increases in lipids, hepatic enzymes, and prolactin, as well as increases in the QT interval. [see WARNINGS AND PRECAUTIONS, and Vital Signs and Laboratory Studies]. The frequency of weight gain ≥ 7%, and the magnitude and frequency of increases in lipids, hepatic analytes, and prolactin in children and adolescents treated with SYMBYAX were similar to those observed in adolescents treated with olanzapine monotherapy.

The safety and efficacy of olanzapine and fluoxetine in combination for the treatment of bipolar I depression in patients under the age of 10 years have not been established. The safety and effectiveness of olanzapine and fluoxetine in combination for treatment resistant depression in patients less than 18 years of age have not been established.

Anyone considering the use of SYMBYAX in a child or adolescent must balance the potential risks with the clinical need [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Olanzapine Safety and effectiveness of olanzapine in children < 13 years of age have not been established.

Compared to patients from adult clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.

Animal Data

Fluoxetine Juvenile animal toxicity studies were performed for fluoxetine alone. Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5-10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1-2 times the average AUC in pediatric patients at the MRHD of 20mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5-10 times the average AUC in pediatric patients at the MRHD of 20mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose.When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1-0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed.

These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30mg/kg/day doses in this study are approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3-0.8, 1-8, and 3-20 times, respectively, the pediatric exposure at the MRHD.

A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m² basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.

Geriatric Use

Symbyax Clinical studies of SYMBYAX did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see DOSAGE AND ADMINISTRATION].

Olanzapine Of the 2500 patients in premarketing clinical studies with olanzapine, 11% (263 patients) were ≥ 65 years of age. In patients with Schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared with younger patients. Studies in patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with Schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING, DOSAGE AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS].

Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient.

Fluoxetine US fluoxetine clinical studies included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including SYMBYAX, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of the fluoxetinecomponent of SYMBYAX should be used in patients with cirrhosis. Caution is advised when using SYMBYAX in patients with diseases or conditions that could affect its metabolism [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 8/7/2013
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Emotional Wellness

Get tips on therapy and treatment.