Symbyax

Generic Name: olanzapine and fluoxetine hydrochloride
Dosage Form: Capsules

Symbyax Description

Symbyax® (olanzapine and fluoxetine HCl capsules) combines 2 psychotropic agents, olanzapine (the active ingredient in Zyprexa®, and Zyprexa Zydis®) and fluoxetine hydrochloride (the active ingredient in Prozac®, Prozac Weekly™, and Sarafem®).

Olanzapine belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular weight of 312.44.

Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride. The molecular formula is C17H18F3NO•HCl, which corresponds to a molecular weight of 345.79.

The chemical structures are:

Olanzapine is a yellow crystalline solid, which is practically insoluble in water.

Fluoxetine hydrochloride is a white to off–white crystalline solid with a solubility of 14 mg/mL in water.

Symbyax capsules are available for oral administration in the following strength combinations:

	3 mg/25 mg	6 mg/25 mg	6 mg/50 mg	12 mg/25 mg	12 mg/50 mg
olanzapine  equivalent	3	6	6	12	12
fluoxetine base  equivalent	25	25	50	25	50

Each capsule also contains pregelatinized starch, gelatin, dimethicone, titanium dioxide, sodium lauryl sulfate, edible black ink, red iron oxide, yellow iron oxide, and/or black iron oxide.

Symbyax - Clinical Pharmacology

Pharmacodynamics

Although the exact mechanism of Symbyax is unknown, it has been proposed that the activation of 3 monoaminergic neural systems (serotonin, norepinephrine, and dopamine) is responsible for its enhanced antidepressant effect. This is supported by animal studies in which the olanzapine/fluoxetine combination has been shown to produce synergistic increases in norepinephrine and dopamine release in the prefrontal cortex compared with either component alone, as well as increases in serotonin.

Olanzapine is a psychotropic agent with high affinity binding to the following receptors: serotonin 5HT2A/2C, 5HT6, (Ki=4, 11, and 5 nM, respectively), dopamine D1–4 (Ki=11 to 31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1–5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and β–adrenergic receptors (Ki>10 μM). Fluoxetine is an inhibitor of the serotonin transporter and is a weak inhibitor of the norepinephrine and dopamine transporters.

Antagonism at receptors other than dopamine and 5HT2 may explain some of the other therapeutic and side effects of olanzapine. Olanzapine’s antagonism of muscarinic M1–5 receptors may explain its anticholinergic–like effects. The antagonism of histamine H1 receptors by olanzapine may explain the somnolence observed with this drug. The antagonism of α1–adrenergic receptors by olanzapine may explain the orthostatic hypotension observed with this drug. Fluoxetine has relatively low affinity for muscarinic, α1–adrenergic, and histamine H1 receptors.

Pharmacokinetics

Fluoxetine (administered as a 60–mg single dose or 60 mg daily for 8 days) caused a small increase in the mean maximum concentration of olanzapine (16%) following a 5–mg dose, an increase in the mean area under the curve (17%) and a small decrease in mean apparent clearance of olanzapine (16%). In another study, a similar decrease in apparent clearance of olanzapine of 14% was observed following olanzapine doses of 6 or 12 mg with concomitant fluoxetine doses of 25 mg or more. The decrease in clearance reflects an increase in bioavailability. The terminal half–life is not affected, and therefore the time to reach steady state should not be altered. The overall steady–state plasma concentrations of olanzapine and fluoxetine when given as the combination in the therapeutic dose ranges were comparable with those typically attained with each of the monotherapies. The small change in olanzapine clearance, observed in both studies, likely reflects the inhibition of a minor metabolic pathway for olanzapine via CYP2D6 by fluoxetine, a potent CYP2D6 inhibitor, and was not deemed clinically significant. Therefore, the pharmacokinetics of the individual components is expected to reasonably characterize the overall pharmacokinetics of the combination.

Absorption and Bioavailability

Symbyax — Following a single oral 12–mg/50–mg dose of Symbyax, peak plasma concentrations of olanzapine and fluoxetine occur at approximately 4 and 6 hours, respectively. The effect of food on the absorption and bioavailability of Symbyax has not been evaluated. The bioavailability of olanzapine given as Zyprexa, and the bioavailability of fluoxetine given as Prozac were not affected by food. It is unlikely that there would be a significant food effect on the bioavailability of Symbyax.

Olanzapine — Olanzapine is well absorbed and reaches peak concentration approximately 6 hours following an oral dose. Food does not affect the rate or extent of olanzapine absorption when olanzapine is given as Zyprexa. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation.

Fluoxetine — Following a single oral 40–mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. Food does not appear to affect the systemic bioavailability of fluoxetine given as Prozac, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant.

Distribution

Symbyax — The in vitro binding to human plasma proteins of the olanzapine/fluoxetine combination is similar to the binding of the individual components.

Olanzapine — Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1–acid glycoprotein.

Fluoxetine — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1–glycoprotein. The interaction between fluoxetine and other highly protein–bound drugs has not been fully evaluated (see PRECAUTIONS, Drugs tightly bound to plasma proteins).

Metabolism and Elimination

Symbyax — Symbyax therapy yielded steady–state concentrations of norfluoxetine similar to those seen with fluoxetine in the therapeutic dose range.

Olanzapine — Olanzapine displays linear pharmacokinetics over the clinical dosing range. Its half–life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr). Administration of olanzapine once daily leads to steady–state concentrations in about 1 week that are approximately twice the concentrations after single doses. Plasma concentrations, half–life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age (see Special Populations).

Following a single oral dose of 14C–labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10–N–glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4′–N–desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

Direct glucuronidation and CYP450–mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYP1A2, CYP2D6, and the flavin–containing monooxygenase system are involved in olanzapine oxidation. CYP2D6–mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

Fluoxetine — Fluoxetine is a racemic mixture (50/50) of R–fluoxetine and S–fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S–fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.

Fluoxetine is extensively metabolized in the liver to its only identified active metabolite, norfluoxetine, via the CYP2D6 pathway. A number of unidentified metabolites exist.

In animal models, S–norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R– or S–fluoxetine. R–norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

Clinical Issues Related to Metabolism and Elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect the clinical use of Symbyax.

Variability in metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme CYP2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S–fluoxetine at a slower rate and thus achieved higher concentrations of S–fluoxetine. Consequently, concentrations of S–norfluoxetine at steady state were lower. The metabolism of R–fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative nonsaturable pathways (non–CYP2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady–state concentration rather than increasing without limit.

Because the metabolism of fluoxetine, like that of a number of other compounds including TCAs and other selective serotonin antidepressants, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see PRECAUTIONS, Drug Interactions).

Accumulation and slow elimination — The relatively slow elimination of fluoxetine (elimination half–life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half–life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single–dose studies, because the metabolism of fluoxetine is not proportional to dose. However, norfluoxetine appears to have linear pharmacokinetics. Its mean terminal half–life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady–state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.

The long elimination half–lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). 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.

Special Populations

Geriatric

Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of Symbyax may be altered in geriatric patients. Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.

In a study involving 24 healthy subjects, the mean elimination half–life of olanzapine was about 1.5 times greater in elderly subjects (>65 years of age) than in non–elderly subjects (≤65 years of age).

The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half–life and nonlinear disposition of the drug, a single–dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age–associated pattern of adverse events was observed in those elderly patients.

Renal Impairment

The pharmacokinetics of Symbyax has not been studied in patients with renal impairment. However, olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. Symbyax dosing adjustment based upon renal impairment is not routinely required.

Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on olanzapine metabolite elimination has not been studied.

In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady–state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

Hepatic Impairment

Based on the individual pharmacokinetic profiles of olanzapine and fluoxetine, the pharmacokinetics of Symbyax may be altered in patients with hepatic impairment. The lowest starting dose should be considered for patients with hepatic impairment (see PRECAUTIONS, Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION, Special Populations).

Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (N=6) with clinically significant cirrhosis (Childs–Pugh Classification A and B) revealed little effect on the pharmacokinetics of olanzapine.

As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half–life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects.

Gender

Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.

Smoking Status

Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely required.

Race

No Symbyax pharmacokinetic study was conducted to investigate the effects of race. In vivo studies have shown that exposures to olanzapine are similar among Japanese, Chinese and Caucasians, especially after normalization for body weight differences. Dosage modifications for race, therefore, are not routinely required.

Combined Effects

The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance of olanzapine in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Symbyax dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of the olanzapine component (see DOSAGE AND ADMINISTRATION, Special Populations).

Clinical Studies

The efficacy of Symbyax for the treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed, 8–week, randomized, double–blind, controlled studies of patients who met Diagnostic and Statistical Manual 4th edition (DSM–IV) criteria for Bipolar I Disorder, Depressed utilizing flexible dosing of Symbyax (6/25, 6/50, or 12/50 mg/day), olanzapine (5 to 20 mg/day), and placebo. These studies included patients (≥18 years of age) with or without psychotic symptoms and with or without a rapid cycling course.

The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery–Asberg Depression Rating Scale (MADRS), a 10–item clinician–rated scale with total scores ranging from 0 to 60. The primary outcome measure of these studies was the change from baseline to endpoint in the MADRS total score. In both studies, Symbyax was statistically significantly superior to both olanzapine monotherapy and placebo in reduction of the MADRS total score. The results of the studies are summarized below (Table 1).

Table 1: MADRS Total Score Mean Change from Baseline to Endpoint

* Negative number denotes improvement from baseline. † Statistically significant compared to both olanzapine and placebo.
	Treatment Group	Baseline Mean	Change to Endpoint Mean*
Study 1	Symbyax    (N=40)	30	-16†
	Olanzapine    (N=182)	32	-12
	Placebo    (N=181)	31	-10
Study 2	Symbyax    (N=42)	32	-18†
	Olanzapine    (N=169)	33	-14
	Placebo    (N=174)	31	-9

Indications and Usage for Symbyax

Symbyax is indicated for the treatment of depressive episodes associated with bipolar disorder. The efficacy of Symbyax was established in 2 identically designed, 8–week, randomized, double–blind clinical studies.

Unlike with unipolar depression, there are no established guidelines for the length of time patients with bipolar disorder experiencing a major depressive episode should be treated with agents containing antidepressant drugs.

The effectiveness of Symbyax for maintaining antidepressant response in this patient population beyond 8 weeks has not been established in controlled clinical studies. Physicians who elect to use Symbyax for extended periods should periodically reevaluate the benefits and long–term risks of the drug for the individual patient.

Contraindications

Hypersensitivity — Symbyax is contraindicated in patients with a known hypersensitivity to the product or any component of the product.

Monoamine Oxidase Inhibitors (MAOI) — There have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with an MAOI, and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Symbyax should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half–lives, at least 5 weeks [perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination)] should be allowed after stopping Symbyax before starting an MAOI.

Pimozide — Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Thioridazine — Thioridazine should not be administered with Symbyax or administered within a minimum of 5 weeks after discontinuation of Symbyax (see WARNINGS, Thioridazine).

Warnings

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 18–24) 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 2.

Table 2

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 PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Symbyax, for a description of the risks of discontinuation of Symbyax).

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 the pediatric population.

Screening Patients for Bipolar Disorder — 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 mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above 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 use in treating bipolar depression.

Increased Mortality in Elderly Patients with Dementia–Related Psychosis — Elderly patients with dementia–related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Symbyax (olanzapine and fluoxetine HCl) is not approved for the treatment of patients with dementia–related psychosis (see BOX WARNING).

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, in Elderly Patients with Dementia–Related Psychosis — 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 is not approved for the treatment of patients with dementia–related psychosis.

Hyperglycemia — 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia–related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment–emergent hyperglycemia–related adverse events 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 two highest serum concentrations was 15.0 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 statistically significantly greater mean change in random glucose compared to placebo (8.65 mg/dL versus –3.86 mg/dL). In patients with baseline normal random glucose levels (<140 mg/dL), 2.3% of those treated with Symbyax were found to have high glucose levels (≥200 mg/dL) during Symbyax treatment and were statistically significantly different compared to 0.3% of those treated with placebo. In patients with baseline borderline random glucose levels (≥140 mg/dL and <200 mg/dL), 34.1% of those treated with Symbyax were found to have high glucose levels (≥200 mg/dL) during Symbyax treatment and were statistically significantly different compared to 3.6% of those treated with placebo. 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 events, 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). These patients had a greater mean increase in HbA1c.

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).

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. In an analysis of 3 placebo–controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a statistically significantly greater mean change in fasting glucose levels compared to placebo (2.68 mg/dL versus –2.59 mg/dL). In patients with baseline normal fasting glucose levels (<100 mg/dL), zero out of 124 (0%) of those treated with olanzapine were found to have high glucose levels (≥126 mg/dL) during olanzapine treatment versus 1 out of 53 (1.9%) of those treated with placebo. In patients with baseline borderline fasting glucose levels (≥100 mg/dL and <126 mg/dL), 2 out of 14 (14.3%) of those treated with olanzapine were found to have high glucose levels (≥126 mg/dL) during olanzapine treatment versus zero out of 13 (0%) of those treated with placebo.

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 with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics 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.

Hyperlipidemia — Undesirable alterations in lipids have been observed with Symbyax use. Clinical monitoring, including baseline and follow-up lipid evaluations in patients using Symbyax, is advised.

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

Controlled fasting lipid data is limited for Symbyax.

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 a statistically significantly different 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 3 shows categorical changes in nonfasting lipid values.

Table 3: Changes in Nonfasting Lipids Values from Controlled Clinical Studies with Treatment Duration up to 12 Weeks

* Statistically significant compared to olanzapine. † Statistically significant compared to placebo.
Laboratory Analyte	Category Change from Baseline	Treatment Arm	N	Patients
Nonfasting Triglycerides	Increase by ≥50 mg/dL	OFC	174	67.8%
		Olanzapine	172	72.7%
	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	15.1%
		Olanzapine	103	8.7%
Nonfasting Total Cholesterol	Increase by ≥40 mg/dL	OFC	685	35%*†
		Olanzapine	749	22.7%
		Placebo	390	9%
	Normal to High (<200 mg/dL to ≥240 mg/dL)	OFC	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)	OFC	213	36.2%*†
		Olanzapine	261	27.6%
		Placebo	111	9.9%

Controlled 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 statistically significant 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 statistically significant 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 events, patients treated with lipid lowering agents, patients with high baseline lipid levels. Table 4 shows categorical changes in fasting lipid values.

Table 4: Changes in Fasting Lipids Values from Adult Placebo-Controlled Olanzapine Monotherapy Studies with Treatment Duration up to 12 Weeks

* Statistically significant compared to placebo.
Laboratory Analyte	Category Change from Baseline	Treatment Arm	N	Patients
Fasting Triglycerides	Increase by ≥50 mg/dL	Olanzapine	745	39.6%*
		Placebo	402	26.1%
	Normal to High (<150 mg/dL to ≥200 mg/dL)	Olanzapine	457	9.2%*
		Placebo	251	4.4%
	Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	135	39.3%*
		Placebo	65	20.0%
Fasting Total Cholesterol	Increase by ≥40 mg/dL	Olanzapine	745	21.6%*
		Placebo	402	9.5%
	Normal to High (<200 mg/dL to ≥240 mg/dL)	Olanzapine	392	2.8%
		Placebo	207	2.4%
	Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)	Olanzapine	222	23.0%*
		Placebo	112	12.5%
Fasting LDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	536	23.7%*
		Placebo	304	14.1%
	Normal to High (<100 mg/dL to ≥160 mg/dL)	Olanzapine	154	0%
		Placebo	82	1.2%
	Borderline to High (≥100 mg/dL and <160 mg/dL to ≥160 mg/dL)	Olanzapine	302	10.6%
		Placebo	173	8.1%

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.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. In an analysis of 3 placebo–controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), for fasting HDL cholesterol, no statistically significant differences were observed between olanzapine–treated patients and placebo–treated patients. Table 5 shows categorical changes in fasting lipid values in adolescent patients.

Table 5: Changes in Fasting Lipids Values from Adolescent Placebo-Controlled Olanzapine Monotherapy Studies

* Statistically significant compared to placebo.
Laboratory Analyte	Category Change from Baseline	Treatment Arm	N	Patients
Fasting Triglycerides	Increase by ≥50 mg/dL	Olanzapine	138	37%*
		Placebo	66	15.2%
	Normal to High (<90 mg/dL to ≥130 mg/dL)	Olanzapine	67	26.9%
		Placebo	28	10.7%
	Borderline to High (≥90 mg/dL and <130 mg/dL to ≥130 mg/dL)	Olanzapine	37	59.5%
		Placebo	17	35.3%
Fasting Total Cholesterol	Increase by ≥40 mg/dL	Olanzapine	138	14.5%*
		Placebo	66	4.5%
	Normal to High (<170 mg/dL to ≥200 mg/dL)	Olanzapine	87	6.9%
		Placebo	43	2.3%
	Borderline to High (≥170 mg/dL and <200 mg/dL to ≥200 mg/dL)	Olanzapine	36	38.9%*
		Placebo	13	7.7%
Fasting LDL Cholesterol	Increase by ≥30 mg/dL	Olanzapine	137	17.5%
		Placebo	63	11.1%
	Normal to High (<110 mg/dL to ≥130 mg/dL)	Olanzapine	98	5.1%
		Placebo	44	4.5%
	Borderline to High (≥110 mg/dL and <130 mg/dL to ≥130 mg/dL)	Olanzapine	29	48.3%*
		Placebo	9	0%

Weight Gain — Potential consequences of weight gain should be considered prior to starting Symbyax. Patients receiving Symbyax should receive regular monitoring of weight.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, the mean weight increase for Symbyax–treated patients was statistically significantly greater than placebo-treated patients (4 kg vs –0.3 kg). Twenty-two percent of Symbyax–treated patients gained at least 7% of their baseline weight, with a median exposure of 6 weeks. This was statistically significantly greater than in placebo-treated patients (1.8%). Approximately three percent of Symbyax–treated patients gained at least 15% of their baseline weight, with a median exposure of 8 weeks. This was statistically significantly 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 zero placebo-treated patients.

Table 6 includes data on weight gain with olanzapine pooled from 68 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Table 6: Weight Gain with Olanzapine Use

Amount Gained kg (lb)	6 Weeks (N=2976) (%)	6 Months (N=1536) (%)	12 Months (N=778) (%)	24 Months (N=422) (%)
≤0	27	21	20	22
0–5 (0–11 lb)	57	34	25	22
5–10 (11–22 lb)	15	26	25	22
10–15 (22–33 lb)	2	12	16	18
>15 (>33 lb)	0	6	14	16

During long-term continuation therapy with olanzapine monotherapy (238 median days of exposure), 56% of olanzapine patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long–term therapy was 5.4 kg.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. In an analysis of 4 placebo–controlled olanzapine monotherapy studies of adolescent patients (ages 13 to 17 years), including those with schizophrenia (6 weeks) or bipolar disorder (manic or mixed episodes) (3 weeks), olanzapine–treated patients gained an average of 4.6 kg, which was statistically significantly different compared to an average of 0.3 kg in placebo–treated patients, with a median exposure of 3 weeks; 40.6% of olanzapine–treated patients gained at least 7% of their baseline body weight, which was statistically significantly different compared to 9.8% of placebo–treated patients, with a median exposure of 4 weeks; 7.1% of olanzapine–treated patients gained at least 15% of their baseline weight, compared to 2.7% of placebo–treated patients, with a median exposure of 19 weeks. Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories, but mean changes in weight were greater in adolescents with BMI categories above normal at baseline. Discontinuation due to weight gain occurred in 1% of olanzapine–treated patients, compared to zero placebo–treated patients.

During long–term continuation therapy with olanzapine, 65% of olanzapine–treated patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long–term therapy was 7.4 kg.

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 bipolar depression studies, statistically significantly more orthostatic changes occurred with the Symbyax group compared to placebo and olanzapine groups. Orthostatic systolic blood pressure decrease of at least 30 mm Hg occurred in 7.3% (6/82), 1.4% (5/346), and 1.4% (5/352) of the Symbyax, olanzapine and placebo groups, respectively. Among the group of controlled clinical studies with Symbyax, an orthostatic systolic blood pressure decrease of ≥30 mm Hg occurred in 4% (21/512) of Symbyax–treated patients, 5% (10/204) of fluoxetine–treated patients, 2% (16/644) of olanzapine–treated patients, and 2% (8/445) of placebo–treated patients. In this group of studies, the incidence of syncope in Symbyax–treated patients was 0.4% (2/571) compared to placebo 0.2% (1/477).

In a clinical pharmacology study of Symbyax, three 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 three other healthy subjects treated with various formulations of olanzapine (one oral, two 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 0.4% (2/549) in the Symbyax group, 0.2% (1/455) in the placebo group, 0.8% (5/659) in the olanzapine group, and 0% (0/241) 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).

Allergic Events and Rash — In Symbyax premarketing controlled clinical studies, the overall incidence of rash or allergic events 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, three patients discontinued (one due to rash, which was moderate in severity, and two due to allergic events, one 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 events 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 events, possibly related to vasculitis, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events.

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

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

Whether these systemic events 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 events 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.

Serotonin Syndrome — The development of a potentially life–threatening serotonin syndrome may occur with SNRIs and SSRIs, including Symbyax treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Symbyax with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors (MAOI) and PRECAUTIONS, Drug Interactions).

If concomitant treatment of Symbyax with a 5–hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions).

The concomitant use of Symbyax with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions).

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.

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) 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.

Thioridazine — In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25–mg oral dose of thioridazine produced a 2.4–fold higher Cmax and a 4.5–fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS).

Thioridazine administration produces a dose–related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes–type arrhythmias and sudden death. This risk is expected to increase with fluoxetine–induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS, Thioridazine).

Precautions

General

Concomitant Use of Olanzapine and Fluoxetine Products — Symbyax contains the same active ingredients that are in Zyprexa and Zyprexa Zydis (olanzapine) and in Prozac, Prozac Weekly, and Sarafem (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with Symbyax.

Abnormal Bleeding — SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. 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 events related to SSRIs and SNRIs 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).

Mania/Hypomania — In the two controlled bipolar depression studies there was no statistically significant difference in the incidence of manic events (manic reaction or manic depressive reaction) between Symbyax– and placebo–treated patients. In one of the studies, the incidence of manic events was (7% [3/43]) in Symbyax–treated patients compared to (3% [5/184]) in placebo–treated patients. In the other study, the incidence of manic events was (2% [1/43]) in Symbyax–treated patients compared to (8% [15/193]) in placebo–treated patients. This limited controlled trial experience of Symbyax in the treatment of bipolar depression makes it difficult to interpret these findings until additional data is obtained. Because of this and the cyclical nature of bipolar disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with Symbyax.

Body Temperature Regulation — 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).

Cognitive and Motor Impairment — Somnolence was a commonly reported adverse event associated with Symbyax treatment, occurring at an incidence of 22% in Symbyax patients compared with 11% in placebo patients. Somnolence led to discontinuation in 2% (10/571) of patients in the premarketing controlled clinical studies.

As with any CNS–active drug, 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.

Discontinuation of Treatment with Symbyax

During marketing of fluoxetine, a component of Symbyax, and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events 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 events 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).

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. Olanzapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Half–Life — 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 (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

Hyperprolactinemia — As with other drugs that antagonize dopamine D2 receptors, Symbyax elevates prolactin levels, and a modest elevation persists during administration; however, possibly associated clinical manifestations (e.g., galactorrhea and breast enlargement) were infrequently observed.

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 of this type. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin–elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. 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 Carcinogenesis). However, neither clinical studies nor epidemiologic studies 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.

Hyponatremia — Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including 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 Symbyax was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). 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.

Seizures — Seizures occurred in 0.2% (4/2066) of Symbyax–treated patients during open–label premarketing clinical studies. No seizures occurred in the premarketing controlled Symbyax studies. Seizures have also been reported with both olanzapine and fluoxetine monotherapy. Therefore, Symbyax should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years of age.

Transaminase Elevations — As with olanzapine, asymptomatic elevations of hepatic transaminases [ALT (SGPT), AST (SGOT), and GGT] and alkaline phosphatase have been observed with Symbyax. In the Symbyax–controlled database, ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 6.3% (31/495) of patients exposed to Symbyax compared with 0.5% (2/384) of the placebo patients and 4.5% (25/560) of olanzapine–treated patients. The difference between Symbyax and placebo was statistically significant. None of these 31 Symbyax–treated patients experienced jaundice and three had transient elevations >200 IU/L.

In olanzapine placebo–controlled studies, clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to olanzapine compared with 0% (0/115) of the placebo patients. None of these patients experienced jaundice. In 2 of these patients, liver enzymes decreased toward normal despite continued treatment, and in 2 others, enzymes decreased upon discontinuation of olanzapine. In the remaining 2 patients, 1, seropositive for hepatitis C, had persistent enzyme elevations for 4 months after discontinuation, and the other had insufficient follow–up to determine if enzymes normalized.

Within the larger olanzapine premarketing database of about 2400 patients with baseline SGPT ≤90 IU/L, the incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued. Among all 2500 patients in olanzapine clinical studies, approximately 1% (23/2500) discontinued treatment due to transaminase increases.

Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre–existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs. Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Laboratory Tests).

Use in Patients with Concomitant Illness

Clinical experience with Symbyax in patients with concomitant systemic illnesses is limited (see CLINICAL PHARMACOLOGY, Renal Impairment and Hepatic Impairment). 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 events possibly related to cholinergic antagonism. Such adverse events 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.

In five placebo–controlled studies of olanzapine in elderly patients with dementia–related psychosis (n=1184), the following treatment–emergent adverse events 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 events 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. If the prescriber elects to treat elderly patients with dementia–related psychosis, vigilance should be exercised (see BOX WARNING and WARNINGS).

As with other CNS–active drugs, Symbyax should be used with caution in elderly patients with dementia. Olanzapine 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 BOX WARNING and WARNINGS).

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.

Caution is advised when using Symbyax in cardiac patients and in patients with diseases or conditions that could affect hemodynamic responses (see WARNINGS, Orthostatic Hypotension).

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 dose of the fluoxetine–component 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 CLINICAL PHARMACOLOGY, Hepatic Impairment and DOSING AND ADMINISTRATION, Special Populations).

Olanzapine and fluoxetine individual pharmacokinetics do not differ significantly in patients with renal impairment. Symbyax dosing adjustment based upon renal impairment is not routinely required (see CLINICAL PHARMACOLOGY, Renal Impairment).

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Symbyax and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Symbyax. The prescriber or health professional 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. The complete text of the Medication Guide is reprinted at the end of this document.

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

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.

Hyperglycemia — Patients should be advised of the potential risk of hyperglycemia–related adverse events. Patients should be monitored regularly for worsening of glucose control.

Weight Gain — Patients should be counseled that Symbyax is associated with weight gain. Patients should have their weight monitored regularly.

Serotonin Syndrome — Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Symbyax and triptans, tramadol or other serotonergic agents.

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 has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding).

Alcohol — Patients should be advised to avoid alcohol while taking Symbyax.

Cognitive and Motor Impairment — As with any CNS–active drug, 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.

Concomitant Medication — Patients should be advised to inform their physician if they are taking Prozac®, Prozac Weekly™, Sarafem®, fluoxetine, Zyprexa®, or Zyprexa Zydis®. Patients should also be advised to inform their physicians if they are taking or plan to take any prescription or over–the–counter drugs, including herbal supplements, since there is a potential for interactions.

Heat Exposure and Dehydration — Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

Nursing — Patients, if taking Symbyax, should be advised not to breast–feed.

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 Drug Interactions).

Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during Symbyax therapy.

Rash — Patients should be advised to notify their physician if they develop a rash or hives while taking Symbyax.

Treatment Adherence — 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.

Patient information is printed at the end of this insert. Physicians should discuss this information with their patients and instruct them to read the Medication Guide before starting therapy with Symbyax and each time their prescription is refilled.

Laboratory Tests

Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Transaminase Elevations).

Drug Interactions

The risks of using Symbyax in combination with other drugs have not been extensively evaluated in systematic studies. The drug–drug interactions of the individual components are applicable to Symbyax. As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. Caution is advised if the concomitant administration of Symbyax and other CNS–active drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination).

Antihypertensive agents — Because of the potential for olanzapine to induce hypotension, Symbyax may enhance the effects of certain antihypertensive agents (see WARNINGS, Orthostatic Hypotension).

Anti–Parkinsonian — The olanzapine component of Symbyax may antagonize the effects of levodopa and dopamine agonists.

Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N–desmethyldiazepam. However, the coadministration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine.

When concurrently administered with fluoxetine, the half–life of diazepam may be prolonged in some patients (see CLINICAL PHARMACOLOGY, Accumulation and slow elimination). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Biperiden — Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden.

Carbamazepine — Carbamazepine therapy (200 mg BID) causes an approximate 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Clozapine — Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine.

Electroconvulsive therapy (ECT) — There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment (see Seizures).

Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics. The coadministration of ethanol with Symbyax may potentiate sedation and orthostatic hypotension.

Fluvoxamine — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of the olanzapine component of Symbyax should be considered in patients receiving concomitant treatment with fluvoxamine.

Haloperidol — Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine.

Lithium — Multiple doses of olanzapine did not influence the pharmacokinetics of lithium.

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored in patients taking Symbyax concomitantly with lithium.

Monoamine oxidase inhibitors — See CONTRAINDICATIONS.

Phenytoin — Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine.

Pimozide — Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS).

Serotonergic drugs — Based on the mechanism of action of SNRIs and SSRIs, including Symbyax, and the potential for serotonin syndrome, caution is advised when Symbyax is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non–selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of Symbyax with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan).

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Thioridazine — See CONTRAINDICATIONS and WARNINGS, Thioridazine.

Tricyclic antidepressants (TCAs) — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

In two fluoxetine studies, previously stable plasma levels of imipramine and desipramine have increased >2– to 10–fold when fluox