Symbyax

Mechanism Of Action

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. In animal studies, olanzapine and fluoxetine in 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.

Pharmacodynamics

Olanzapine binds with high affinity 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

SYMBYAX - 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.

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 olanzapine and fluoxetine in 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 DRUG INTERACTIONS].

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 DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

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.

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 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.

Specific Populations

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 reactions was observed in those elderly patients.

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.

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 DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

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 (Child-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.

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.

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

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.

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].

Based on the pediatric SYMBYAX study, steady-state olanzapine, fluoxetine, and norfluoxetine plasma concentrations were about 31%, 76%, and 38% higher, respectively, in pediatric patients with lower body weights (less than 50 kg) than in pediatric patients with high body weight (greater than or equal to 50 kg). Exposures in pediatric patients with high body weight were similar to those previously observed in adults. Dose modifications based on body weight are not required.

Clinical Studies

Efficacy for SYMBYAX was established for the:

• Acute treatment of depressive episodes in Bipolar I Disorder in adults, and children and adolescents (10 to 17 years) in 3 short-term, placebo-controlled trials (Studies 1, 2, 3) [see Clinical Studies].
• Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials (Studies 4, 5, 6) and 1 randomized withdrawal study with an active control (Study 7) [see Clinical Studies].

Depressive Episodes Associated With Bipolar I Disorder

Adults - The efficacy of SYMBYAX for the acute treatment of depressive episodes associated with Bipolar I 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 [n=788]) 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. Refer to Table 18 (Studies 1 and 2).

Children and Adolescents - The efficacy of SYMBYAX for the acute treatment of depressive episodes associated with Bipolar I Disorder was established in a single 8-week, randomized, double-blind, placebo-controlled study of patients, 10 to 17 years of age [N=255], who met Diagnostic and Statistical Manual 4th edition-Text Revision (DSM-IVTR) criteria for Bipolar I Disorder, Depressed. Patients were initiated at a dose of 3/25 mg/day and force-titrated to the maximum dose of 12/50 mg/day over two weeks. After Week 2, there was flexible dosing of SYMBYAX in the range of 6/25, 6/50, 12/25, or 12/50 mg/day. The average daily dose was olanzapine 7.7 mg and fluoxetine 37.6 mg. The recommended starting dose for children and adolescents is 3/25 mg per day. Flexible dosing is recommended, rather than the forced titration used in the study [see DOSAGE AND ADMINISTRATION]. This study included patients with or without psychotic symptoms.

The primary rating instrument used to assess depressive symptoms in these studies was the Children's Depressive Rating Scale-Revised (CDRS-R), a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary outcome measure of this study was the change from baseline to Week 8 in the CDRS-R total score. In this study, SYMBYAX was statistically significantly superior to placebo in reduction of the CDRS-R total score. Refer to Table 18 (Study 3).

Table 18: Summary of the Primary Efficacy Result for Studies in Bipolar Depressiona

Treatment Resistant Depression

The efficacy of SYMBYAX in acute treatment resistant depression was demonstrated with data from 3 clinical studies (n=579) in adults (18 to 85 years). Doses evaluated in these studies ranged from 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine.

An 8-week randomized, double-blind controlled study was conducted to evaluate the efficacy of SYMBYAX in patients (n=300) who met DSM-IV criteria for Major Depressive Disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode. Patients who were not responding to an antidepressant in their current episode entered an 8-week open-label fluoxetine lead-in; non-responders were randomized (1:1:1) to receive SYMBYAX, olanzapine, or fluoxetine, and were treated for 8 weeks. SYMBYAX was flexibly dosed between 6/50 mg, 12/50 mg, and 18/50 mg. Results from this study yielded statistically significant greater reduction in mean total MADRS scores from baseline to endpoint for SYMBYAX versus fluoxetine and olanzapine. See Table 19 (Study 4). A second study with the same treatment-resistant patient population (n=28), when analyzed with change in MADRS as the outcome measure, demonstrated statistically significantly greater reduction in MADRS scores for SYMBYAX versus fluoxetine and olanzapine. See Table 19 (Study 5). A third study demonstrated statistically significantly greater reduction in total MADRS scores for SYMBYAX versus fluoxetine or olanzapine alone, when analyzed in a subpopulation of depressed patients (n=251) who met the definition of treatment resistance (patients who had not responded to 2 antidepressants of adequate dose and duration in the current episode). See Table 19 (Study 6).

Table 19: Summary of the Primary Efficacy Result for Studies in Treatment-Resistant Depressiona

The efficacy of SYMBYAX in the maintenance therapy of treatment-resistant depression was demonstrated in a 47-week study (Study 7) in adults (18 to 65 years). SYMBYAX was dosed between 6/25 mg, 12/25 mg, 6/50 mg, 12/50 mg, and 18/50 mg.

Patients (N=892) met DSM-IV criteria for Major Depressive Disorder and for treatment-resistant depression (a lack of response to 2 antidepressants after at least 6 weeks at or above the minimally effective labeled dose in their current episode of major depressive disorder). Patients were initially treated with open-label SYMBYAX; those who responded to and were stabilized on treatment over approximately 20 weeks were randomized to continue receiving treatment with SYMBYAX (n=221) or to receive treatment with fluoxetine (n=223) for another 27 weeks. Relapse wasassessed using 3 criteria: a 50% increase in Montgomery-Åsberg Depression Rating Scale score from randomization with concomitant Clinical Global Impressions-Severity of Depression score increase to 4 or more; hospitalization due to depression or suicidality; or discontinuation due to lack of efficacy/worsening of depression/suicidality. A total of 15.8% of patients on SYMBYAX and 31.8% of patients on fluoxetine relapsed; this difference was statistically significant. Patients receiving continued SYMBYAX experienced statistically significantly longer time to relapse over the 27 weeks compared with those receiving fluoxetine (Figure 1).

Figure 1 : Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Study 7)

Symbyax is part of the drug class:

• Antidepressants in combination with psycholeptics

Grapefruit and grapefruit juice may interact with the olanzapine in this product and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Take Symbyax exactly as prescribed. It may take a few weeks to notice the effects of this medication.

Do not stop taking Symbyax abruptly. If your doctor needs to lower your dose, he or she will lower your dose gradually.

Symbyax comes in capsule form and is taken once daily.

Take with water in the evening. You should drink plenty of water while you are being treated with Symbyax.

Alcohol may intensify some of the side effects of this medication.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Symbyax at the same time.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• body aches or pain
• confusion
• congestion
• cough
• delusions
• dementia
• dryness or soreness of the throat
• fever
• hoarseness
• rapid weight gain
• runny nose
• shakiness in the legs, arms, hands, or feet
• tender, swollen glands in the neck
• tingling of the hands or feet
• trembling or shaking of the hands or feet
• trouble with swallowing
• unusual weight gain or loss
• voice changes

• Blurred vision
• change in personality
• change in vision
• difficult or labored breathing
• difficulty with sleeping
• difficulty with speaking
• dizziness
• ear pain
• headache
• impaired vision
• increase in body movements
• loss of memory
• nervousness
• pounding in the ears
• problems with memory
• slow, fast, pounding, or irregular heartbeat or pulse
• tightness in the chest

• Inability to move the eyes
• increased blinking or spasms of the eyelid
• sticking out of the tongue
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual facial expressions

• Bloody or black, tarry stools
• constipation
• severe stomach pain
• vomiting of blood or material that looks like coffee grounds

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• dry mouth
• increased appetite
• lack or loss of strength
• weight gain

• Change or problem with discharge of semen
• decreased interest in sexual intercourse
• difficulty with moving
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• muscle pain or stiffness
• not able to have an orgasm
• pain, swelling, or redness in the joints
• tooth disorder
• twitching

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use Symbyax as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take in the evening.
• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Tell all of your health care providers that you take Symbyax. This includes your doctors, nurses, pharmacists, and dentists.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Symbyax, you will want to slowly stop it as ordered by your doctor.
• Avoid drinking alcohol while taking this medicine.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• Check your blood sugar as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

You should not use this medicine if you also take pimozide or thioridazine, or if you take fluoxetine or olanzapine in a non-combination form (Prozac, Zyprexa, and others).

Serious drug interactions can occur when certain medicines are used with fluoxetine and olanzapine. Tell your doctor about all your current medicines and any you start or stop using.

Some young people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using Symbyax. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Symbyax should not be given to a child younger than 10 years old.

This medicine is not approved for use in psychotic conditions related to dementia. Symbyax may increase the risk of death in older adults with dementia-related conditions.

You should not use this medicine if you also take pimozide or thioridazine, or if you take other forms of fluoxetine or olanzapine (such as Prozac, Rapiflux, Sarafem, Selfemra, or Zyprexa).

Do not use this medicine if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, and tranylcypromine. Do not take an MAO inhibitor within 5 weeks after you stop taking Symbyax.

Symbyax is not approved for use in psychotic conditions related to dementia. Fluoxetine and olanzapine may increase the risk of death in older adults with dementia-related conditions.

To make sure this medicine is safe for you, tell your doctor if you have:

• liver disease;

• diabetes, high cholesterol or triglycerides;

• seizures or epilepsy;

• narrow-angle glaucoma;

• heart disease, high or low blood pressure, history of heart attack or stroke;

• history of "mini-stroke" or "TIA" or if you have recently had a heart attack;

• personal or family history of long QT syndrome;

• low levels of potassium or magnesium in your blood;

• a bleeding or blood-clotting disorder;

• an enlarged prostate, bowel obstruction, or severe constipation;

• breast cancer; or

• a history of drug abuse or suicidal thoughts.

Some young people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using Symbyax. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Taking this medication during pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking Symbyax, do not stop taking it without your doctor's advice.

Fluoxetine and olanzapine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are taking this medication.

This medicine should not be given to a child younger than 10 years old.

Take Symbyax exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Symbyax with or without food. Take the medicine at the same time each day.

It may take up to 4 weeks before your symptoms improve. Tell your doctor if your symptoms do not improve.

Store at room temperature away from moisture and heat.

Drinking alcohol can increase certain side effects of fluoxetine and olanzapine.

Ask your doctor before taking a nonsteroidal anti-inflammatory drug (NSAID), including aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex), diclofenac, indomethacin, meloxicam, and others. Using this medicine with an NSAID may cause you to bruise or bleed easily.

Avoid driving or operating machinery until you know how this medicine will affect you. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Dizziness or severe drowsiness can cause falls, fractures, or other injuries.

Applies to fluoxetine / olanzapine: oral capsule

Along with its needed effects, fluoxetine / olanzapine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking fluoxetine / olanzapine:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• body aches or pain
• confusion
• congestion
• cough
• delusions
• dementia
• dryness or soreness of the throat
• fever
• hoarseness
• rapid weight gain
• runny nose
• shakiness in the legs, arms, hands, or feet
• tender, swollen glands in the neck
• tingling of the hands or feet
• trembling or shaking of the hands or feet
• trouble with swallowing
• unusual weight gain or loss
• voice changes

• Blurred vision
• change in personality
• change in vision
• difficult or labored breathing
• difficulty with sleeping
• difficulty with speaking
• dizziness
• ear pain
• headache
• impaired vision
• increase in body movements
• loss of memory
• nervousness
• pounding in the ears
• problems with memory
• slow, fast, pounding, or irregular heartbeat or pulse
• tightness in the chest

• Inability to move the eyes
• increased blinking or spasms of the eyelid
• sticking out of the tongue
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual facial expressions

• Bloody or black, tarry stools
• constipation
• severe stomach pain
• vomiting of blood or material that looks like coffee grounds

Some side effects of fluoxetine / olanzapine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• dry mouth
• increased appetite
• lack or loss of strength
• weight gain

• Change or problem with discharge of semen
• decreased interest in sexual intercourse
• difficulty with moving
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• muscle pain or stiffness
• not able to have an orgasm
• pain, swelling, or redness in the joints
• tooth disorder
• twitching