Symbyax (olanzapine 12 mg fluoxetine hydrochloride 25 mg) Dailymed

Recent Major Changes Section

Warnings and Precautions (5.6, 5.16)

08/2023

• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.3)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue if DRESS is suspected (5.4)
• Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain (5.5)
  • Hyperglycemia and Diabetes Mellitus :In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death. Monitor for symptoms of hyperglycemia. Perform fasting blood glucose testing before beginning, and periodically during treatment. (5.5)
  • Dyslipidemia : Appropriate clinical monitoring is recommended, including fasting blood lipid testing before beginning, and periodically during, treatment (5.5)
  • Weight gain : Consider potential consequences of weight gain. Monitor weight regularly (5.5)
• Serotonin Syndrome : Serotonin syndrome has been reported with SSRIs and SNRIs, including SYMBYAX, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue SYMBYAX and serotonergic agents and initiate supportive treatment. If concomitant use of SYMBYAX with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.6).
• Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.7)
• Allergic Reactions and Rash : Discontinue upon appearance of rash or allergic phenomena (5.8)
• Activation of Mania/Hypomania : Screen for Bipolar Disorder and monitor for activation of mania/hypomania (5.9)
• Tardive Dyskinesia : Discontinue if clinically appropriate (5.10)
• Orthostatic Hypotension : Can be associated with bradycardia and syncope. Risk is increased during initial dose titration. Use caution in patients with cardiovascular disease or cerebrovascular disease, and those conditions that could affect hemodynamic responses (5.11)
• Leukopenia, Neutropenia, and Agranulocytosis : Has been reported with antipsychotics, including SYMBYAX. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy. Consider discontinuing SYMBYAX at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.13)
• Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.15)
• Increased Risk of Bleeding : SSRIs increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.16)
• Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing SYMBYAX if symptomatic hyponatremia occurs (SIADH) (5.17)
• Potential for Cognitive and Motor Impairment : Has potential to impair judgment, thinking, and motor skills. Caution patients about operating machinery (5.18)
• QT Prolongation : QT prolongation and ventricular arrhythmia including Torsade de Pointes have been reported with fluoxetine. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.20)
• Anticholinergic (antimuscarinic) Effects : Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, history of paralytic ileus or related conditions (5.21)
• Hyperprolactinemia : May elevate prolactin levels (5.22)
• Long Elimination Half-Life of Fluoxetine : Changes in dose will not be fully reflected in plasma for several weeks (5.24)
• Sexual Dysfunction : SYMBYAX use may cause symptoms of sexual dysfunction (5.26)

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

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 [see Warnings and Precautions (5.25)].

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 (8.4)].

5.2 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

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 Use in Specific Populations (8.5)].

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).

Meta-Analysis of Antipsychotic Use in Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. SYMBYAX (olanzapine and fluoxetine) is not approved for the treatment of patients with dementia-related psychosis [see Use in Specific Populations (8.5)].

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].

5.3 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 Warnings and Precautions (5.5)].

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue SYMBYAX if DRESS is suspected.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine's specific metabolic profile is presented below.

Hyperglycemia and Diabetes Mellitus

Adults — Healthcare providers 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.

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 HbA_1c increase from baseline of 0.15% (median exposure 63 days), compared to a mean HbA_1c decrease of 0.04% in fluoxetine-treated subjects (median exposure 57 days) and a mean HbA_1c 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

a Not Applicable.
			Up to 12 weeks exposure		At least 48 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Random Glucose	Normal to High(<140 mg/dL to ≥200 mg/dL)	SYMBYAX	609	2.3%	382	3.1%
		Placebo	346	0.3%	NAa	NAa
	Borderline to High(≥140 mg/dL and <200 mg/dL to ≥200 mg/dL)	SYMBYAX	44	34.1%	27	37.0%
		Placebo	28	3.6%	NAa	NAa

In a 47-week SYMBYAX study, the mean change from baseline to endpoint in fasting glucose was +4.81 mg/dL (n=130). Table 3 shows the categorical changes in fasting glucose [see Clinical Studies (14.2)].

Table 3: Changes in Fasting Glucose Levels from a Single Adult SYMBYAX Study

a Not Applicable.
			Up to 27 Weeks Exposure(Randomized, Double-Blind Phase)		Up to 47 Weeks Exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High(<100 mg/dL to ≥126 mg/dL)	SYMBYAX	90	4.4%	130	11.5%
		Fluoxetine	96	5.2%	NAa	NAa
	Borderline to High(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	SYMBYAX	98	18.4%	79	32.9%
		Fluoxetine	97	7.2%	NAa	NAa

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 4 shows categorical changes in fasting blood glucose from the pediatric SYMBYAX study.

Table 4: Changes in Fasting Glucose Levels from a Single Pediatric SYMBYAX Study in Bipolar Depression

a Impaired Glucose Tolerance.
			Up to 8 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients
Fasting Glucose	Normal to High(<100 mg/dL to ≥126 mg/dL)	SYMBYAX	125	4.8%
		Placebo	65	1.5%
	Normal/IGTa to High(<126 mg/dL to ≥126 mg/dL)	SYMBYAX	156	5.8%
		Placebo	78	1.3%
	Normal/IGT (<126 mg/dL) to ≥140 mg/dL)	SYMBYAX	156	1.9%
		Placebo	78	0.0%

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 5 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 5: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

a Not Applicable.
			Up to 12 weeks exposure		At least 24 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High(<100 mg/dL to ≥126 mg/dL)	Olanzapine	124	0%	108	0.9%
		Placebo	53	1.9%	NAa	NAa
	Borderline to High(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)	Olanzapine	14	14.3%	13	23.1%
		Placebo	13	0%	NAa	NAa

Dyslipidemia

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.

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 6 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 6: 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
NonfastingTriglycerides	Increase by ≥50 mg/dL	SYMBYAX	174	67.8%
		Olanzapine	172	72.7%
	Normal to High(<150 mg/dL to ≥500 mg/dL)	SYMBYAX	57	0%
		Olanzapine	58	0%
	Borderline to High(≥150 mg/dL and <500 mg/dL to ≥500 mg/dL)	SYMBYAX	106	15.1%
		Olanzapine	103	8.7%
NonfastingTotal Cholesterol	Increase by ≥40 mg/dL	SYMBYAX	685	35%
		Olanzapine	749	22.7%
		Placebo	390	9%
	Normal to High(<200 mg/dL to ≥240 mg/dL)	SYMBYAX	256	8.2%
		Olanzapine	279	2.9%
		Placebo	175	1.7%
	Borderline to High(≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)	SYMBYAX	213	36.2%
		Olanzapine	261	27.6%
		Placebo	111	9.9%

A 47-week SYMBYAX study demonstrated mean changes from baseline to endpoint in fasting total cholesterol (+1.24 mg/dL), LDL cholesterol (+0.29 mg/dL), direct HDL cholesterol (-2.13 mg/dL), and triglycerides (+11.33 mg/dL). Table 7 shows the categorical changes in fasting lipids [see Clinical Studies (14.2)].

Table 7: Changes in Fasting Lipids Values from a Controlled Study with SYMBYAX Treatment Duration up to 47 Weeks

a Not Applicable.
			Up to 27 Weeks Treatment(Randomized, Double-Blind Phase)		Up to 47 Weeks Treatment
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Total Cholesterol	Normal to High (<200 mg/dL to ≥240 mg/dL)	SYMBYAX	47	2.1%	83	19.3%
		Fluoxetine	59	3.4%	NAa	NAa
	Borderline to High (≥200 and <240 mg/dL to ≥240 mg/dL)	SYMBYAX	75	28.0%	73	69.9%
		Fluoxetine	83	20.5%	NAa	NAa
Fasting LDL Cholesterol	Normal to High(<100 mg/dL to ≥160 mg/dL)	SYMBYAX	22	4.5%	46	8.7%
		Fluoxetine	26	0%	NAa	NAa
	Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)	SYMBYAX	115	17.4%	128	46.9%
		Fluoxetine	134	10.4%	NAa	NAa
Fasting HDLCholesterol	Normal to Low(≥40 mg/dL to <40 mg/dL)	SYMBYAX	199	39.2%	193	45.1%
		Fluoxetine	208	25.5%	NAa	NAa
Fasting Triglycerides	Normal to High(<150 mg/dL to ≥200 mg/dL)	SYMBYAX	68	16.2%	115	46.1%
		Fluoxetine	74	5.4%	NAa	NAa
	Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)	SYMBYAX	47	51.1%	40	72.5%
		Fluoxetine	41	26.8%	NAa	NAa

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 8 shows categorical changes in fasting lipids values.

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

a Not Applicable.
			Up to 12 weeks exposure		At least 48 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
	Increase by ≥50 mg/dL	Olanzapine	745	39.6%	487	61.4%
		Placebo	402	26.1%	NAa	NAa
Fasting	Normal to High	Olanzapine	457	9.2%	293	32.4%
Triglycerides	(<150 mg/dL to ≥200 mg/dL)	Placebo	251	4.4%	NAa	NAa
	Borderline to High	Olanzapine	135	39.3%	75	70.7%
	(≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)	Placebo	65	20.0%	NAa	NAa
	Increase by ≥40 mg/dL	Olanzapine	745	21.6%	489	32.9%
		Placebo	402	9.5%	NAa	NAa
Fasting	Normal to High	Olanzapine	392	2.8%	283	14.8%
Total Cholesterol	(<200 mg/dL to ≥240 mg/dL)	Placebo	207	2.4%	NAa	NAa
	Borderline to High	Olanzapine	222	23.0%	125	55.2%
	(≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)	Placebo	112	12.5%	NAa	NAa
	Increase by ≥30 mg/dL	Olanzapine	536	23.7%	483	39.8%
		Placebo	304	14.1%	NAa	NAa
Fasting	Normal to High	Olanzapine	154	0%	123	7.3%
LDL Cholesterol	(<100 mg/dL to ≥160 mg/dL)	Placebo	82	1.2%	NAa	NAa
	Borderline to High	Olanzapine	302	10.6%	284	31.0%
	(≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)	Placebo	173	8.1%	NAa	NAa

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 9 shows categorical changes in fasting lipids values from the pediatric SYMBYAX study.

Table 9: 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
FastingTriglycerides	Increase by ≥50 mg/dL	SYMBYAX	158	70.3%
		Placebo	81	38.3%
	Normal to High(<90 mg/dL to ≥130 mg/dL)	SYMBYAX	71	39.4%
		Placebo	31	19.4%
	Borderline to High(≥90 mg/dL and <130 mg/dL to ≥130 mg/dL)	SYMBYAX	13	84.6%
		Placebo	12	33.3%
	Normal/borderline to High(<130 mg/dL to ≥130 mg/dL)	SYMBYAX	106	52.8%
		Placebo	56	25.0%
	Normal to borderline/high(<90 mg/dL to ≥90 mg/dL)	SYMBYAX	71	73.2%
		Placebo	31	41.9%
	Normal/borderline/high to very high(<500 mg/dL to ≥500 mg/dL)	SYMBYAX	158	2.5%
		Placebo	81	1.2%
FastingTotal Cholesterol	Increase by ≥40 mg/dL	SYMBYAX	158	52.5%
		Placebo	81	8.6%
	Normal to High(<170 mg/dL to ≥200 mg/dL)	SYMBYAX	81	12.3%
		Placebo	44	4.5%
	Borderline to High(≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)	SYMBYAX	22	72.7%
		Placebo	11	24.3%
	Normal/borderline to High(<200 mg/dL to ≥200 mg/dL)	SYMBYAX	126	32.5%
		Placebo	67	10.4%
	Normal to borderline/high(<170 mg/dL to ≥170 mg/dL)	SYMBYAX	81	58.0%
		Placebo	44	31.8%
FastingLDL Cholesterol	Increase by ≥30 mg/dL	SYMBYAX	158	53.8%
		Placebo	81	23.5%
	Normal to High(<110 mg/dL to ≥130 mg/dL)	SYMBYAX	112	13.4%
		Placebo	62	6.5%
	Borderline to High(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)	SYMBYAX	12	75.0%
		Placebo	3	0.0%
	Normal/borderline to High(<130 mg/dL to ≥130 mg/dL)	SYMBYAX	138	21.7%
		Placebo	77	7.8%
	Normal to borderline/high(<110 mg/dL to ≥110 mg/dL)	SYMBYAX	112	30.4%
		Placebo	62	14.5%

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 10 shows categorical changes in fasting lipids values in adolescents.

Table 10: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

a Not Applicable.
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
FastingTriglycerides	Increase by ≥50 mg/dL	Olanzapine	138	37.0%	122	45.9%
		Placebo	66	15.2%	NAa	NAa
	Normal to High(<90 mg/dL to >130 mg/dL)	Olanzapine	67	26.9%	66	36.4%
		Placebo	28	10.7%	NAa	NAa
	Borderline to High(≥90 mg/dL and ≤130 mg/dL to >130 mg/dL)	Olanzapine	37	59.5%	31	64.5%
		Placebo	17	35.3%	NAa	NAa
FastingTotal Cholesterol	Increase by ≥40 mg/dL	Olanzapine	138	14.5%	122	14.8%
		Placebo	66	4.5%	NAa	NAa
	Normal to High(<170 mg/dL to ≥200 mg/dL)	Olanzapine	87	6.9%	78	7.7%
		Placebo	43	2.3%	NAa	NAa
	Borderline to High(≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	36	38.9%	33	57.6%
		Placebo	13	7.7%	NAa	NAa
FastingLDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	137	17.5%	121	22.3%
		Placebo	63	11.1%	NAa	NAa
	Normal to High(<110 mg/dL to ≥130 mg/dL)	Olanzapine	98	5.1%	92	10.9%
		Placebo	44	4.5%	NAa	NAa
	Borderline to High(≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)	Olanzapine	29	48.3%	21	47.6%
		Placebo	9	0%	NAa	NAa

Weight Gain

Potential consequences of weight gain should be considered prior to starting SYMBYAX. Patients receiving SYMBYAX should receive regular monitoring of weight.

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.

Table 11 presents the distribution of weight gain in a single long-term relapse prevention study of patients treated for up to 47 weeks with SYMBYAX [see Clinical Studies (14.2)].

Table 11: Weight Gain with SYMBYAX Use in a Single Relapse Prevention Study in Adults

Amount Gained kg (lb)	Up to 8 Weeks (N=881) (%)	Up to 20 Weeks (N=651) (%)	Up to 47 Weeks (N=220) (%)
≤0	19.8	14.9	19.1
0 to ≤5 (0-11 lb)	64.1	47.2	37.7
>5 to ≤10 (11-22 lb)	15.1	30.3	27.7
>10 to ≤15 (22-33 lb)	0.9	5.8	10.0
>15 to ≤20 (33-44 lb)	0.1	1.2	3.2
>20 to ≤25 (44-55 lb)	0.0	0.6	1.4
>25 to ≤30 (55-66 lb)	0.0	0.0	0.5
>30 (>66 lb)	0.0	0.0	0.5

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 12 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 12: Weight Gain with Olanzapine Use in Adults

Amount Gainedkg (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
0 to ≤5 (0-11 lb)	57.0	36.0	26.0	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	17.0
>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

Dose group differences with respect to weight gain have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day.

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 13 depicts weight gain observed in the pediatric SYMBYAX study.

Table 13: Weight Gain with SYMBYAX Use Seen in a Single Pediatric Study in Bipolar Depression

Amount Gainedkg (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 14: 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 15 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 15: Weight Gain with Olanzapine Use in Adolescents

Amount Gainedkg (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	22.0
>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

5.6 Serotonin Syndrome

Selective serotonin reuptake inhibitors (SSRIs), including SYMBYAX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4.1), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and 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).

The concomitant use of SYMBYAX with MAOIs is contraindicated. In addition, do not initiate SYMBYAX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking SYMBYAX, discontinue SYMBYAX before initiating treatment with the MAOI [see Contraindications (4.1) and Drug Interations (7.1)].

Monitor all patients taking SYMBYAX for the emergence of serotonin syndrome. Discontinue treatment with SYMBYAX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of SYMBYAX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.7 Angle-Closure Glaucoma

Angle-Closure Glaucoma — The pupillary dilation that occurs following use of many antidepressant drugs including SYMBYAX may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.8 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.

5.9 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.

5.10 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.

Tardive dyskinesia 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.

5.11 Orthostatic Hypotension

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

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).

5.12 Falls

SYMBYAX may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.13 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.

5.14 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.

5.15 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.

5.16 Increased Risk of 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. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. 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 increased risk of bleeding associated with the concomitant use of SYMBYAX and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

5.17 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 (8.5)]. 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.

5.18 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.

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.

5.19 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).

5.20 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 (4.2), Adverse Reactions (6), Drug Interactions (7.7, 7.8), Overdosage (10.1), and Clinical Pharmacology (12.3)].

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 (7.7, 7.8) and Clinical Pharmacology (12.3)].

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 QT_c interval for patients treated with SYMBYAX compared with patients on placebo: mean change in QT_cF (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 QT_c increases ≥60 msec or QT_c ≥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 (6.1)].

5.21 Anticholinergic (antimuscarinic) Effects

The following precautions for the individual components may be applicable to SYMBYAX.

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 a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, a history of paralytic ileus, or related conditions.

5.22 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 (13.1)]. 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 dysmenorrhea, galactorrhea, 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 (8.4)].

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

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

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

Dose group differences with respect to prolactin elevation have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (n=199), 20 (n=200) and 40 (n=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.23 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^®, and Sarafem^® (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with SYMBYAX [see Overdosage (10)].

5.24 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 (12.3)].

5.25 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 healthcare provider 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 (2.4)].

5.26 Sexual Dysfunction

Use of SSRIs, including fluoxetine a component of SYMBYAX, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SYMBYAX use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SYMBYAX use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of SYMBYAX and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.