These Highlights Do Not Include All The Information Needed To Use Fluoxetine Capsules, Safely And Effectively. See Full Prescribing Information For Fluoxetine Capsules.

Initial Treatment

In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. Fluoxetine should be introduced with care in patients with a history of seizures.

The following have been reported with fluoxetine overdosage:

• Seizures, which may be delayed, and altered mental status including coma.
• Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, torsade de pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
• Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk).

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a fluoxetine overdose.

Consider contacting a Poison Center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

Fluoxetine capsules, USP are a selective serotonin reuptake inhibitor for oral administration. It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C₁₇H₁₈F₃NO∙HCl. Its molecular weight is 345.79. The structural formula is:

Fluoxetine hydrochloride, USP is a white to off-white crystalline powder with a solubility of 14 mg/mL in water.

Each capsule contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The capsules also contain the following inactive ingredients: pregelatinized starch (maize [corn]), colloidal silicon dioxide, gelatin, sodium lauryl sulphate, FD&C Blue #1, FD&C Red #3, and titanium dioxide. In addition 20 mg capsules also contains D&C Yellow #10 and 10 mg capsules also contains FD&C Yellow #6. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. 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 fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of fluoxetine 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.

Fluoxetine Capsules, USP

(floo ox' e teen)

Read the Medication Guide that comes with fluoxetine capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

What is the most important information I should know about fluoxetine capsules?

Fluoxetine capsules and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

• Fluoxetine capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice:
  • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
  • Pay particular attention to such changes when fluoxetine capsules are started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry or irritable
• trouble sleeping
• an increase in activity or talking more than what is normal for you
• other unusual changes in behavior or mood

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine capsules may be associated with these serious side effects:

2. Serotonin Syndrome. This condition can be life-threatening and may include:

• agitation, hallucinations, coma or other changes in mental status
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
• dizziness
• flushing
• tremor
• seizures

3. Severe allergic reactions:

• trouble breathing
• swelling of the face, tongue, eyes or mouth
• rash, itchy welts (hives) or blisters, alone or with fever or joint pain

4. Abnormal bleeding: Fluoxetine capsules and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin^®, Jantoven^®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

5. Visual problems:

• eye pain
• changes in vision
• swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

6. Seizures or convulsions

7. Manic episodes:

• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual

8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems

10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include:

• fast, slow, or irregular heartbeat
• shortness of breath
• dizziness or fainting

11. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, may cause sexual problems.

• Symptoms in males may include:
  • Delayed ejaculation or inability to have an ejaculation
  • Decreased sex drive
  • Problems getting or keeping an erection
• Symptoms in females may include:
  • Decreased sex drive
  • Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluoxetine. There may be treatments your healthcare provider can suggest.

Do not stop fluoxetine capsules without first talking to your healthcare provider. Stopping fluoxetine capsules too quickly may cause serious symptoms including:

• anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking, confusion

What are fluoxetine capsules?

Fluoxetine capsules are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.

Fluoxetine capsules are used to treat:

• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Bulimia Nervosa
  Not approved for use in children
• Panic Disorder
• Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa)
• Treatment Resistant Depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Zyprexa)

Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine capsules treatment.

Who should not take fluoxetine capsules?

Do not take fluoxetine capsules if you:

• are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine capsules. See the end of this Medication Guide for a complete list of ingredients in fluoxetine capsules.
• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
  • Do not take an MAOI within 5 weeks of stopping fluoxetine capsules unless directed to do so by your physician.
  • Do not start fluoxetine capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

People who take fluoxetine capsules close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

•  
  • high fever
  • uncontrolled muscle spasms
  • stiff muscles
  • rapid changes in heart rate or blood pressure
  • confusion
  • loss of consciousness (pass out)

• take Mellaril^® (thioridazine). Do not take Mellaril^® within 5 weeks of stopping fluoxetine capsules because this can cause serious heart rhythm problems or sudden death.
• take the antipsychotic medicine pimozide (Orap^®) because this can cause serious heart problems.

What should I tell my healthcare provider before taking fluoxetine capsules? Ask if you are not sure.

Before starting fluoxetine capsules, tell your healthcare provider if you:

• Are taking certain drugs or treatments such as:
  • Triptans used to treat migraine headache
  • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics
  • Amphetamines
  • Tramadol and fentanyl
  • Over-the-counter supplements such as tryptophan or St. John's Wort
  • Electroconvulsive therapy (ECT)
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• are pregnant or plan to become pregnant. Taking fluoxetine capsules late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
  • If you become pregnant while taking fluoxetine capsules , talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or go to https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants /.
• are breast-feeding or plan to breast-feed. Fluoxetine capsules may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if taking fluoxetine capsules.

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fluoxetine capsules and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine capsules with your other medicines. Do not start or stop any medicine while taking fluoxetine capsules without talking to your healthcare provider first.

If you take fluoxetine capsules, you should not take any other medicines that contain fluoxetine hydrochloride including:

How should I take fluoxetine capsules?

• Take fluoxetine capsules exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine capsules until it is the right dose for you.
• Fluoxetine capsules may be taken with or without food.
• If you miss a dose of fluoxetine capsules, 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 fluoxetine capsules at the same time.
• If you take too much fluoxetine capsules, call your healthcare provider or poison control center right away, or get emergency treatment.

What should I avoid while taking fluoxetine capsules?

Fluoxetine capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluoxetine capsules affects you. Do not drink alcohol while using fluoxetine capsules.

What are the possible side effects of fluoxetine capsules?

Fluoxetine capsules may cause serious side effects, including:

• See "What is the most important information I should know about fluoxetine capsules?"
• Problems with blood sugar control. People who have diabetes and take fluoxetine capsules may have problems with low blood sugar while taking fluoxetine capsules. High blood sugar can happen when fluoxetine capsules are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine capsules.
• Feeling anxious or trouble sleeping

Common possible side effects in people who take fluoxetine capsules include:

• unusual dreams
• sexual problems
• loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth
• flu symptoms
• feeling tired or fatigued
• change in sleep habits
• yawning
• sinus infection or sore throat
• tremor or shaking
• sweating
• feeling anxious or nervous
• hot flashes
• rash

Other side effects in children and adolescents include:

• increased thirst
• abnormal increase in muscle movement or agitation
• nose bleed
• urinating more often
• heavy menstrual periods
• possible slowed growth rate and weight change. Your child's height and weight should be monitored during treatment with fluoxetine capsules.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluoxetine capsules. For more information, ask your healthcare provider or pharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.

How should I store fluoxetine capsules?

• Store fluoxetine capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature].
• Keep fluoxetine capsules away from light.
• Keep fluoxetine capsules bottle closed tightly.

Keep fluoxetine capsules and all medicines out of the reach of children.

General information about fluoxetine capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine capsules for a condition for which it was not prescribed. Do not give fluoxetine capsules to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about fluoxetine capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine capsules that is written for healthcare professionals.

For more information about fluoxetine capsules call Westminster Pharmaceuticals, LLC at 1-844-221-7294.

What are the ingredients in fluoxetine capsules?

Active ingredient: fluoxetine hydrochloride, USP

Inactive ingredients: pregelatinized starch (maize [corn]), colloidal silicon dioxide, gelatin, sodium lauryl sulphate, FD&C Blue #1, FD&C Red #3, and titanium dioxide. In addition 20 mg capsules also contains D&C Yellow #10 and 10 mg capsules also contains FD&C Yellow #6. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

All trademarks are the property of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

ScieGen Pharmaceuticals Inc

Hauppauge, NY 11788

USA

Manufactured for:

Westminster Pharmaceuticals, LLC

Nashville, TN 37217

Rev. 11/2021

US fluoxetine clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)].

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients.

Efficacy for fluoxetine was established for the:

• Acute and maintenance treatment of Major Depressive Disorder in adults, and children and adolescents (8 to 18 years) in 7 short-term and 2 long-term, placebo-controlled trials [see Clinical Studies (14.1)].
• Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with Obsessive Compulsive Disorder (OCD) in 3 short-term placebo-controlled trials [see Clinical Studies (14.2)].
• Acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa in 3 short-term and 1 long-term, placebo-controlled trials [see Clinical Studies (14.3)].
• Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in 2 short-term, placebo-controlled trials [see Clinical Studies (14.4)].

Efficacy for fluoxetine and olanzapine in combination 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.
• Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials and 1 randomized withdrawal study with an active control.

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia.

Study 1 (N = 180 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 mg/day to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.

Study 2 (N = 214 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 mg/day to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

When using fluoxetine capsules and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Allergic Reactions and Rash [see Warnings and Precautions (5.3)]
• Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4)]
• Seizures [see Warnings and Precautions (5.5)]
• Altered Appetite and Weight [see Warnings and Precautions (5.6)]
• Abnormal Bleeding [see Warnings and Precautions (5.7)]
• Angle-Closure Glaucoma [see Warnings and Precautions (5.8)]
• Hyponatremia [see Warnings and Precautions (5.9)]
• Anxiety and Insomnia [see Warnings and Precautions (5.10)]
• QT Prolongation [see Warnings and Precautions (5.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)]
• Discontinuation Adverse Reactions [see Warnings and Precautions (5.15)]
• Sexual Dysfunction [see Warnings and Precautions (5.17)]

When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for 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.

The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 mg/day or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging.

In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or healthcare provider judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.

Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications (4.2), Adverse Reactions (6.2), Drug Interactions (7.7, 7.8), Overdosage (10), and Clinical Pharmacology (12.3)].

Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3)].

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

Caution is advised if the concomitant administration of fluoxetine and such 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 (12.3)].

Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.

Antagonism of muscarinic, histaminergic, and α₁-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

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

Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

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

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

The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.9, 2.10)].

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

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

[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)].

Fluoxetine is indicated for the treatment of:

• Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies (14.1)].
• Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD)[see Clinical Studies (14.2)].
• Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)].
• Acute treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4)].

Fluoxetine and Olanzapine in Combination is indicated for the treatment of:

• Acute treatment of depressive episodes associated with Bipolar I Disorder.
• Treatment resistant depression (Major Depressive Disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode).

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression.

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax^® .

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

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

Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.

In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5].

When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

• A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7)

Fluoxetine capsules and olanzapine in combination:

• Dosage adjustments should be made with the individual components according to efficacy and tolerability (2.5, 2.6)
• Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6)
• Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults (2.5, 2.6)
• Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 (2.5)

The use of fluoxetine is contraindicated with the following:

• Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)]
• Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)]

Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.

• Fluoxetine capsules, USP 10 mg
  Fluoxetine base equivalent.
  are white to off white powder filled in size "4" hard gelatin capsules with opaque light blue colored cap and opaque light orange colored body imprinted "SG" on cap and "113" on body with black ink.
• Fluoxetine capsules, USP 20 mg
  are white to off white powder filled in size "2" hard gelatin capsules with opaque light blue colored cap and opaque light green colored body imprinted "SG" on cap and "114" on body with black ink.
• Fluoxetine capsules, USP 40 mg
  are white to off white powder filled in size "0" hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted "SG" on cap and "115" on body with black ink.

The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation

When using fluoxetine and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)].

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

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

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

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

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

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

Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.

In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.

Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.15)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine as monotherapy or in combination with olanzapine. When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

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.

Product: 50090-6574

NDC: 50090-6574-0 30 CAPSULE in a BOTTLE

NDC: 50090-6574-1 60 CAPSULE in a BOTTLE

NDC: 50090-6574-3 90 CAPSULE in a BOTTLE

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

Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].

The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)].

Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.10) and Warnings and Precautions (5.2)].

• Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)].
• In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)].
• Fluoxetine is not approved for use in children less than 7 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

When using fluoxetine and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax.

Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.

Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

As with any CNS-active drug, fluoxetine 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 the drug treatment does not affect them adversely.

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)].

Do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].

In some cases, a patient already receiving fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluoxetine is unclear. The healthcare provider should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

When using Fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Adjust dosage, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 mg to 50 mg and oral olanzapine 5 mg to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 mg to 18 mg and fluoxetine 25 mg to 50 mg.

Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability.

Periodically re-examine the need for continued pharmacotherapy.

Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Fluoxetine monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 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 1,000 pati ents treated) are provided in Table 2.

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

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

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

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

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

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.15)].

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 fluoxetine 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 fluoxetine is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder; and fluoxetine in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I 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 for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

Initial Treatment

In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. Fluoxetine should be introduced with care in patients with a history of seizures.

The following have been reported with fluoxetine overdosage:

• Seizures, which may be delayed, and altered mental status including coma.
• Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, torsade de pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
• Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk).

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a fluoxetine overdose.

Consider contacting a Poison Center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

Fluoxetine capsules, USP are a selective serotonin reuptake inhibitor for oral administration. It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C₁₇H₁₈F₃NO∙HCl. Its molecular weight is 345.79. The structural formula is:

Fluoxetine hydrochloride, USP is a white to off-white crystalline powder with a solubility of 14 mg/mL in water.

Each capsule contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The capsules also contain the following inactive ingredients: pregelatinized starch (maize [corn]), colloidal silicon dioxide, gelatin, sodium lauryl sulphate, FD&C Blue #1, FD&C Red #3, and titanium dioxide. In addition 20 mg capsules also contains D&C Yellow #10 and 10 mg capsules also contains FD&C Yellow #6. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, healthcare providers should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. 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 fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of fluoxetine 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.

Fluoxetine Capsules, USP

(floo ox' e teen)

Read the Medication Guide that comes with fluoxetine capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

What is the most important information I should know about fluoxetine capsules?

Fluoxetine capsules and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

• Fluoxetine capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice:
  • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
  • Pay particular attention to such changes when fluoxetine capsules are started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry or irritable
• trouble sleeping
• an increase in activity or talking more than what is normal for you
• other unusual changes in behavior or mood

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine capsules may be associated with these serious side effects:

2. Serotonin Syndrome. This condition can be life-threatening and may include:

• agitation, hallucinations, coma or other changes in mental status
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
• dizziness
• flushing
• tremor
• seizures

3. Severe allergic reactions:

• trouble breathing
• swelling of the face, tongue, eyes or mouth
• rash, itchy welts (hives) or blisters, alone or with fever or joint pain

4. Abnormal bleeding: Fluoxetine capsules and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin^®, Jantoven^®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

5. Visual problems:

• eye pain
• changes in vision
• swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

6. Seizures or convulsions

7. Manic episodes:

• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual

8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems

10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include:

• fast, slow, or irregular heartbeat
• shortness of breath
• dizziness or fainting

11. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, may cause sexual problems.

• Symptoms in males may include:
  • Delayed ejaculation or inability to have an ejaculation
  • Decreased sex drive
  • Problems getting or keeping an erection
• Symptoms in females may include:
  • Decreased sex drive
  • Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluoxetine. There may be treatments your healthcare provider can suggest.

Do not stop fluoxetine capsules without first talking to your healthcare provider. Stopping fluoxetine capsules too quickly may cause serious symptoms including:

• anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking, confusion

What are fluoxetine capsules?

Fluoxetine capsules are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.

Fluoxetine capsules are used to treat:

• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Bulimia Nervosa
  Not approved for use in children
• Panic Disorder
• Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa)
• Treatment Resistant Depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Zyprexa)

Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine capsules treatment.

Who should not take fluoxetine capsules?

Do not take fluoxetine capsules if you:

• are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine capsules. See the end of this Medication Guide for a complete list of ingredients in fluoxetine capsules.
• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
  • Do not take an MAOI within 5 weeks of stopping fluoxetine capsules unless directed to do so by your physician.
  • Do not start fluoxetine capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

People who take fluoxetine capsules close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

•  
  • high fever
  • uncontrolled muscle spasms
  • stiff muscles
  • rapid changes in heart rate or blood pressure
  • confusion
  • loss of consciousness (pass out)

• take Mellaril^® (thioridazine). Do not take Mellaril^® within 5 weeks of stopping fluoxetine capsules because this can cause serious heart rhythm problems or sudden death.
• take the antipsychotic medicine pimozide (Orap^®) because this can cause serious heart problems.

What should I tell my healthcare provider before taking fluoxetine capsules? Ask if you are not sure.

Before starting fluoxetine capsules, tell your healthcare provider if you:

• Are taking certain drugs or treatments such as:
  • Triptans used to treat migraine headache
  • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics
  • Amphetamines
  • Tramadol and fentanyl
  • Over-the-counter supplements such as tryptophan or St. John's Wort
  • Electroconvulsive therapy (ECT)
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• are pregnant or plan to become pregnant. Taking fluoxetine capsules late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
  • If you become pregnant while taking fluoxetine capsules , talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or go to https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants /.
• are breast-feeding or plan to breast-feed. Fluoxetine capsules may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if taking fluoxetine capsules.

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fluoxetine capsules and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine capsules with your other medicines. Do not start or stop any medicine while taking fluoxetine capsules without talking to your healthcare provider first.

If you take fluoxetine capsules, you should not take any other medicines that contain fluoxetine hydrochloride including:

How should I take fluoxetine capsules?

• Take fluoxetine capsules exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine capsules until it is the right dose for you.
• Fluoxetine capsules may be taken with or without food.
• If you miss a dose of fluoxetine capsules, 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 fluoxetine capsules at the same time.
• If you take too much fluoxetine capsules, call your healthcare provider or poison control center right away, or get emergency treatment.

What should I avoid while taking fluoxetine capsules?

Fluoxetine capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluoxetine capsules affects you. Do not drink alcohol while using fluoxetine capsules.

What are the possible side effects of fluoxetine capsules?

Fluoxetine capsules may cause serious side effects, including:

• See "What is the most important information I should know about fluoxetine capsules?"
• Problems with blood sugar control. People who have diabetes and take fluoxetine capsules may have problems with low blood sugar while taking fluoxetine capsules. High blood sugar can happen when fluoxetine capsules are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine capsules.
• Feeling anxious or trouble sleeping

Common possible side effects in people who take fluoxetine capsules include:

• unusual dreams
• sexual problems
• loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth
• flu symptoms
• feeling tired or fatigued
• change in sleep habits
• yawning
• sinus infection or sore throat
• tremor or shaking
• sweating
• feeling anxious or nervous
• hot flashes
• rash

Other side effects in children and adolescents include:

• increased thirst
• abnormal increase in muscle movement or agitation
• nose bleed
• urinating more often
• heavy menstrual periods
• possible slowed growth rate and weight change. Your child's height and weight should be monitored during treatment with fluoxetine capsules.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluoxetine capsules. For more information, ask your healthcare provider or pharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.

How should I store fluoxetine capsules?

• Store fluoxetine capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature].
• Keep fluoxetine capsules away from light.
• Keep fluoxetine capsules bottle closed tightly.

Keep fluoxetine capsules and all medicines out of the reach of children.

General information about fluoxetine capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine capsules for a condition for which it was not prescribed. Do not give fluoxetine capsules to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about fluoxetine capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine capsules that is written for healthcare professionals.

For more information about fluoxetine capsules call Westminster Pharmaceuticals, LLC at 1-844-221-7294.

What are the ingredients in fluoxetine capsules?

Active ingredient: fluoxetine hydrochloride, USP

Inactive ingredients: pregelatinized starch (maize [corn]), colloidal silicon dioxide, gelatin, sodium lauryl sulphate, FD&C Blue #1, FD&C Red #3, and titanium dioxide. In addition 20 mg capsules also contains D&C Yellow #10 and 10 mg capsules also contains FD&C Yellow #6. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

All trademarks are the property of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

ScieGen Pharmaceuticals Inc

Hauppauge, NY 11788

USA

Manufactured for:

Westminster Pharmaceuticals, LLC

Nashville, TN 37217

Rev. 11/2021

US fluoxetine clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)].

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients.

Efficacy for fluoxetine was established for the:

• Acute and maintenance treatment of Major Depressive Disorder in adults, and children and adolescents (8 to 18 years) in 7 short-term and 2 long-term, placebo-controlled trials [see Clinical Studies (14.1)].
• Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with Obsessive Compulsive Disorder (OCD) in 3 short-term placebo-controlled trials [see Clinical Studies (14.2)].
• Acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa in 3 short-term and 1 long-term, placebo-controlled trials [see Clinical Studies (14.3)].
• Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in 2 short-term, placebo-controlled trials [see Clinical Studies (14.4)].

Efficacy for fluoxetine and olanzapine in combination 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.
• Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials and 1 randomized withdrawal study with an active control.

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia.

Study 1 (N = 180 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 mg/day to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.

Study 2 (N = 214 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 mg/day to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

When using fluoxetine capsules and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Allergic Reactions and Rash [see Warnings and Precautions (5.3)]
• Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4)]
• Seizures [see Warnings and Precautions (5.5)]
• Altered Appetite and Weight [see Warnings and Precautions (5.6)]
• Abnormal Bleeding [see Warnings and Precautions (5.7)]
• Angle-Closure Glaucoma [see Warnings and Precautions (5.8)]
• Hyponatremia [see Warnings and Precautions (5.9)]
• Anxiety and Insomnia [see Warnings and Precautions (5.10)]
• QT Prolongation [see Warnings and Precautions (5.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)]
• Discontinuation Adverse Reactions [see Warnings and Precautions (5.15)]
• Sexual Dysfunction [see Warnings and Precautions (5.17)]

When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for 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.

The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 mg/day or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging.

In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or healthcare provider judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.

Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications (4.2), Adverse Reactions (6.2), Drug Interactions (7.7, 7.8), Overdosage (10), and Clinical Pharmacology (12.3)].

Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3)].

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

Caution is advised if the concomitant administration of fluoxetine and such 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 (12.3)].

Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.

Antagonism of muscarinic, histaminergic, and α₁-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

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

Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

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

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

The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.9, 2.10)].

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

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

[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)].

Fluoxetine is indicated for the treatment of:

• Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies (14.1)].
• Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD)[see Clinical Studies (14.2)].
• Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)].
• Acute treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4)].

Fluoxetine and Olanzapine in Combination is indicated for the treatment of:

• Acute treatment of depressive episodes associated with Bipolar I Disorder.
• Treatment resistant depression (Major Depressive Disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode).

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression.

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax^® .

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

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

Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.

In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5].

When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

• A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7)

Fluoxetine capsules and olanzapine in combination:

• Dosage adjustments should be made with the individual components according to efficacy and tolerability (2.5, 2.6)
• Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6)
• Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults (2.5, 2.6)
• Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 (2.5)

The use of fluoxetine is contraindicated with the following:

• Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)]
• Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)]

Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.

• Fluoxetine capsules, USP 10 mg
  Fluoxetine base equivalent.
  are white to off white powder filled in size "4" hard gelatin capsules with opaque light blue colored cap and opaque light orange colored body imprinted "SG" on cap and "113" on body with black ink.
• Fluoxetine capsules, USP 20 mg
  are white to off white powder filled in size "2" hard gelatin capsules with opaque light blue colored cap and opaque light green colored body imprinted "SG" on cap and "114" on body with black ink.
• Fluoxetine capsules, USP 40 mg
  are white to off white powder filled in size "0" hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted "SG" on cap and "115" on body with black ink.

The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation

When using fluoxetine and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)].

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

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

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

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

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

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

Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.

In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.

Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.15)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine as monotherapy or in combination with olanzapine. When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

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.

Product: 50090-6574

NDC: 50090-6574-0 30 CAPSULE in a BOTTLE

NDC: 50090-6574-1 60 CAPSULE in a BOTTLE

NDC: 50090-6574-3 90 CAPSULE in a BOTTLE

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

Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].

The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)].

Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.10) and Warnings and Precautions (5.2)].

• Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)].
• In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)].
• Fluoxetine is not approved for use in children less than 7 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

When using fluoxetine and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax.

Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.

Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

As with any CNS-active drug, fluoxetine 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 the drug treatment does not affect them adversely.

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)].

Do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].

In some cases, a patient already receiving fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluoxetine is unclear. The healthcare provider should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

When using Fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Adjust dosage, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 mg to 50 mg and oral olanzapine 5 mg to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 mg to 18 mg and fluoxetine 25 mg to 50 mg.

Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability.

Periodically re-examine the need for continued pharmacotherapy.

Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Fluoxetine monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 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 1,000 pati ents treated) are provided in Table 2.

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

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

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

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

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

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.15)].

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 fluoxetine 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 fluoxetine is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder; and fluoxetine in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I 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 for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].