NDC 54868-4537 Fluoxetine Hydrochloride

NDC Product Code 54868-4537

NDC CODE: 54868-4537

Proprietary Name: Fluoxetine Hydrochloride What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Product Characteristics

Color(s):
TURQUOISE (C48334 - LIGHT TURQUOISE BLUE OPAQUE)
PINK (C48328 - FLESH OPAQUE)
Shape: CAPSULE (C48336)
Size(s):
16 MM
Imprint(s):
MYLAN;4220
Score: 1

NDC Code Structure

NDC 54868-4537-0

Package Description: 30 CAPSULE in 1 BOTTLE, PLASTIC

NDC 54868-4537-1

Package Description: 60 CAPSULE in 1 BOTTLE, PLASTIC

NDC 54868-4537-2

Package Description: 100 CAPSULE in 1 BOTTLE, PLASTIC

NDC 54868-4537-3

Package Description: 90 CAPSULE in 1 BOTTLE, PLASTIC

NDC 54868-4537-4

Package Description: 240 CAPSULE in 1 BOTTLE, PLASTIC

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Fluoxetine Hydrochloride with NDC 54868-4537 is a product labeled by Physicians Total Care, Inc.. The product's dosage form is and is administered via form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 310385 and 313989.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • GELATIN (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FD&C BLUE NO. 1 (UNII: H3R47K3TBD)
  • FD&C RED NO. 40 (UNII: WZB9127XOA)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • SHELLAC (UNII: 46N107B71O)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Physicians Total Care, Inc.
Labeler Code: 54868
Start Marketing Date: 10-23-2008 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Fluoxetine

Fluoxetine is pronounced as (floo ox' e teen)

Why is fluoxetine medication prescribed?
Fluoxetine (Prozac) is used to treat depression, obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and ov...
[Read More]

* Please review the disclaimer below.

Fluoxetine Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Boxed Warning

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGSAntidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children, adolescents
and young adults in short-term studies of major depressive disorder (MDD) and
other psychiatric disorders. Anyone considering the use of fluoxetine or any
other antidepressant in a child, adolescent or young adult must balance this
risk with the clinical need. 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 in risk with antidepressants compared to placebo
in adults aged 65 and older. Depression and certain other psychiatric disorders
are themselves associated with increases in the risk of suicide. Patients of all
ages who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Fluoxetine is approved for
use in pediatric patients with MDD and obsessive compulsive disorder (OCD) [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®.

Recent Major Changes

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1 Indications And Usage

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1.1 Major Depressive Disorder

Fluoxetine capsules are indicated for the acute and maintenance
treatment of major depressive disorder in adult patients and in pediatric
patients aged 8 to18 years [see Clinical Studies
(14.1)]. The usefulness of the drug in adult and pediatric patients receiving
fluoxetine for extended periods, should periodically be reevaluated [see  Dosage and
Administration (2.1)].

1.2 Obsessive Compulsive Disorder

Fluoxetine capsules are indicated for the acute and maintenance
treatment of obsessions and compulsions in adult patients and in pediatric
patients aged 7 to 17 years with obsessive compulsive disorder (OCD) [see Clinical Studies
(14.2)].The effectiveness of fluoxetine in long-term use, i.e., for more than 13
weeks, has not been systematically evaluated in placebo-controlled trials.
Therefore, the physician who elects to use fluoxetine capsules for extended
periods, should periodically reevaluate the long-term usefulness of the drug for
the individual patient [see Dosage and
Administration (2.2)].

1.3 Bulimia Nervosa

Fluoxetine capsules are indicated for the acute and maintenance
treatment of binge-eating and vomiting behaviors in adult patients with moderate
to severe bulimia nervosa [see Clinical Studies
(14.3)]. The physician who elects to use fluoxetine capsules for extended periods
should periodically reevaluate the long-term usefulness of the drug for the
individual patient [see Dosage and
Administration (2.3)].

1.4 Panic Disorder

Fluoxetine capsules are indicated for the acute treatment of
panic disorder, with or without agoraphobia, in adult patients [see Clinical Studies
(14.4)].The effectiveness of fluoxetine in long-term use, i.e., for more than 12
weeks, has not been established in placebo-controlled trials. Therefore, the
physician who elects to use fluoxetine capsules for extended periods, should
periodically reevaluate the long-term usefulness of the drug for the individual
patient [see  Dosage and
Administration (2.4)].

1.5 Fluoxetine And Olanzapine In Combination: Depressive Episodes Associated With Bipolar I Disorder

When using fluoxetine and olanzapine in combination, also refer to
the Clinical Studies section of the package insert for Symbyax®.  
Fluoxetine and olanzapine in combination is indicated for the acute treatment of
depressive episodes associated with bipolar I disorder in adult patients.
 
Fluoxetine capsule monotherapy is not indicated for the treatment of depressive
episodes associated with bipolar I disorder.

2 Dosage And Administration

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2.1 Major Depressive Disorder

Initial TreatmentAdultIn controlled trials used to support the efficacy of fluoxetine,
patients were administered morning doses ranging from 20 to 80 mg/day. Studies
comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is
sufficient to obtain a satisfactory response in major depressive disorder in
most cases. Consequently, a dose of 20 mg/day, administered in the morning, is
recommended as the initial dose. A dose increase may be considered after several weeks if insufficient
clinical improvement is observed. Doses above 20 mg/day may be administered on a
once-a-day (morning) or BID schedule (i.e., morning and noon) and should not
exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents)In the short-term (8 to 9 week) controlled clinical trials of
fluoxetine supporting its effectiveness in the treatment of major depressive
disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies
(14.1)]. Treatment should be initiated with a dose of 10 or 20
mg/day. After one week at 10 mg/day, the dose should be increased to 20 mg/day.
However, due to higher plasma levels in lower weight children, the starting
and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may
be considered after several weeks if insufficient clinical improvement is
observed. All patientsAs with other drugs effective in the treatment of major
depressive disorder, the full effect may be delayed until 4 weeks of treatment
or longer.Maintenance/Continuation/Extended TreatmentIt is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy.
Whether the dose needed to induce remission is identical to the dose needed to
maintain and/or sustain euthymia is unknown.Daily DosingSystematic evaluation of fluoxetine capsules in adult patients
has shown that its efficacy in major depressive disorder is maintained for
periods of up to 38 weeks following 12 weeks of open-label acute treatment (50
weeks total) at a dose of 20 mg/day [see Clinical Studies
(14.1)].Switching Patients to a Tricyclic Antidepressant
(TCA)Dosage of a TCA may need to be reduced and plasma TCA
concentrations may need to be monitored temporarily when fluoxetine is
coadministered or has been recently discontinued [see Drug Interactions
(7.9)].Switching Patients to or from a Monoamine Oxidase
Inhibitor (MAOI)At least 14 days should elapse between discontinuation of an MAOI
and initiation of therapy with fluoxetine capsules. In addition, at least 5
weeks, perhaps longer, should be allowed after stopping fluoxetine capsules
before starting an MAOI [see  Contraindications
(4) and Drug Interactions
(7.1)].

2.2 Obsessive Compulsive Disorder

Initial TreatmentAdultIn the controlled clinical trials of fluoxetine supporting its
effectiveness in the treatment of OCD, patients were administered fixed daily
doses of 20 mg, 40 mg or 60 mg of fluoxetine or placebo [see
Clinical Studies
(14.2)]. In one of these studies, no dose-response
relationship for effectiveness was demonstrated. Consequently, a dose of 20
mg/day, administered in the morning, is recommended as the initial dose. Since
there was a suggestion of a possible dose-response relationship for
effectiveness in the second study, a dose increase may be considered after
several weeks if insufficient clinical improvement is observed. The full
therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once daily (i.e., morning) or
BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is
recommended; however, doses of up to 80 mg/day have been well tolerated in open
studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day.Pediatric (children and adolescents)In the controlled clinical trial of fluoxetine supporting its
effectiveness in the treatment of OCD, patients were administered fluoxetine
doses in the range of 10 to 60 mg/day [see Clinical Studies
(14.2)].In adolescents and higher weight children, treatment should be initiated with
a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day.
Additional dose increases may be considered after several more weeks if
insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day
is recommended. In lower weight children, treatment should be initiated with a dose of 10
mg/day. Additional dose increases may be considered after several more weeks if
insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day
is recommended. Experience with daily doses greater than 20 mg is very minimal,
and there is no experience with doses greater than 60 mg. Maintenance/Continuation TreatmentWhile there are no systematic studies that answer the question of
how long to continue fluoxetine capsules, OCD is a chronic condition and it is
reasonable to consider continuation for a responding patient. Although the
efficacy of fluoxetine after 13 weeks has not been documented in controlled
trials, adult patients have been continued in therapy under double-blind
conditions for up to an additional 6 months without loss of benefit. However,
dosage adjustments should be made to maintain the patient on the lowest
effective dosage and patients should be periodically reassessed to determine the
need for treatment.

2.3 Bulimia Nervosa

Initial TreatmentIn the controlled clinical trials of fluoxetine supporting its
effectiveness in the treatment of bulimia nervosa, patients were administered
fixed daily fluoxetine doses of 20 mg or 60 mg, or placebo [see Clinical Studies
(14.3)]. Only the 60 mg dose was statistically significantly
superior to placebo in reducing the frequency of binge-eating and vomiting.
Consequently, the recommended dose is 60 mg/day, administered in the morning.
For some patients it may be advisable to titrate up to this target dose over
several days. Fluoxetine doses above 60 mg/day have not been systematically
studied in patients with bulimia.Maintenance/Continuation TreatmentSystematic evaluation of continuing fluoxetine capsules 60 mg/day
for periods of up to 52 weeks in patients with bulimia who have responded while
taking fluoxetine capsules 60 mg/day during an 8-week acute treatment phase has
demonstrated a benefit of such maintenance treatment [see Clinical Studies
(14.3)]. Nevertheless, patients should be periodically reassessed to
determine the need for maintenance treatment.

2.4 Panic Disorder

Initial TreatmentIn the controlled clinical trials of fluoxetine supporting its
effectiveness in the treatment of panic disorder, patients were administered
fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies
(14.4)]. Treatment should be initiated with a dose of 10 mg/day.
After one week, the dose should be increased to 20 mg/day. The most frequently
administered dose in the two flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical
improvement is observed. Fluoxetine doses above 60 mg/day have not been
systematically evaluated in patients with panic disorder. Maintenance/Continuation TreatmentWhile there are no systematic studies that answer the question of
how long to continue fluoxetine capsules, panic disorder is a chronic condition
and it is reasonable to consider continuation for a responding patient.
Nevertheless, patients should be periodically reassessed to determine the need
for continued treatment.

2.5 Fluoxetine And Olanzapine In Combination: Depressive Episodes Associated With Bipolar I Disorder

When using fluoxetine and olanzapine in combination, also refer to
the Clinical Studies section of the package insert for Symbyax®.  
Fluoxetine should be administered 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. Dosage adjustments, if indicated, can be
made according to efficacy and tolerability within dose ranges of fluoxetine 20
mg to 50 mg and oral olanzapine 5 mg to 12.5 mg. Antidepressant efficacy was
demonstrated with olanzapine and fluoxetine in combination with a dose range of
olanzapine 6 mg to 12 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. The following table demonstrates the appropriate individual component
doses of fluoxetine and olanzapine vs. Symbyax®. Dosage adjustments, if indicated, should be made with
the individual components according to efficacy and tolerability. TABLE 1: Approximate Dose Correspondence Between Symbyax®* and the Combination of Fluoxetine and
OlanzapineFor Symbyax®(mg/day)Use in
CombinationOlanzapine(mg/day)Fluoxetine(mg/day)3 mg olanzapine/25 mg
fluoxetine2.5206 mg olanzapine/25 mg
fluoxetine52012 mg olanzapine/25 mg
fluoxetine10 + 2.5206 mg olanzapine/50 mg
fluoxetine540 + 1012 mg olanzapine/50 mg
fluoxetine10 + 2.540 + 10*Symbyax®
(olanzapine/fluoxetine hydrochloride) is a fixed-dose combination of fluoxetine
and olanzapine. While
there is no body of evidence to answer the question of how long a patient
treated with fluoxetine and olanzapine in combination should remain on it, it is
generally accepted that bipolar I disorder, including the depressive episodes
associated with bipolar I disorder, is a chronic illness requiring chronic
treatment. The physician should periodically reexamine 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
capsule monotherapy is not indicated for the treatment of depressive episodes
associated with bipolar I disorder.

2.7 Dosing In Specific Populations

Treatment of Pregnant Women during the Third
TrimesterWhen treating pregnant women with fluoxetine capsules during the
third trimester, the physician should carefully consider the potential risks and
potential benefits of treatment. Neonates exposed to SNRIs or SSRIs late in the
third trimester have developed complications requiring prolonged
hospitalization, respiratory support and tube feeding. The physician may
consider tapering fluoxetine capsules in the third trimester [see Use in Specific
Populations (8.1)]. GeriatricsA lower or less frequent dosage should be considered for the
elderly [see Use in
Specific Populations (8.5)].Hepatic ImpairmentAs with many other medications, a lower or less frequent dosage
should be used in patients with hepatic impairment [see
Clinical
Pharmacology (12.4) and Use in Specific
Populations (8.6)].Concomitant IllnessPatients with concurrent disease or on multiple concomitant
medications may require dosage adjustments [see Clinical
Pharmacology (12.4) and Warnings and
Precautions (5.10)].Fluoxetine and Olanzapine in CombinationThe starting dose of oral olanzapine 2.5 mg to 5 mg with
fluoxetine 20 mg should be used for patients with a predisposition to
hypotensive reactions, patients with hepatic impairment, or patients who exhibit
a combination of factors that may slow the metabolism of olanzapine or
fluoxetine in combination (female gender, geriatric age, nonsmoking status), or
those patients who may be pharmacodynamically sensitive to olanzapine. Dosing
modifications may be necessary in patients who exhibit a combination of factors
that may slow metabolism. When indicated, dose escalation should be performed
with caution in these patients. Fluoxetine and olanzapine in combination have
not been systematically studied in patients over 65 years of age or in patients
less than 18 years of age [see Warnings and
Precautions (5.14) and Drug Interactions
(7.9)].

2.8 Discontinuation Of Treatment

Symptoms associated with discontinuation of fluoxetine, SNRIs and SSRIs, have
been reported [see Warnings and
Precautions (5.13)].

3 Dosage Forms And Strengths

  • 10 mg capsule is a hard-shell gelatin capsule with a white opaque cap and a
  • Flesh opaque body axially printed with MYLAN over 4210 in black ink on both the cap and the body.20 mg capsule is a hard-shell gelatin capsule with a light turquoise blue
  • Opaque cap and a flesh opaque body axially printed with MYLAN over 4220 in black ink on both
  • The cap and the body. 40 mg capsule is a hard-shell gelatin capsule with a light blue opaque cap
  • And a white opaque body axially printed with MYLAN over
  • 4350 in black ink on both the cap and the body.

4 Contraindications

  • When using fluoxetine and olanzapine in combination, also
  • Refer to the Contraindications section of the package insert for Symbyax®. The use of fluoxetine is contraindicated with the following:Monoamine Oxidase Inhibitors [see Drug Interactions
  • (7.1)]Pimozide [see Drug Interactions
  • (7.9)]Thioridazine [see Drug Interactions
  • (7.9)]

5 Warnings And Precautions

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

5.1 Clinical Worsening And Suicide Risk

Patients with major depressive disorder (MDD), both adult and
pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior,
whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of
depression and certain other psychiatric disorders, and these disorders
themselves are the strongest predictors of suicide. There has been a
long-standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients
during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that
these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents and young adults (ages 18 to 24) with major depressive
disorder (MDD) and other psychiatric disorders. Short-term studies did not show
an increase in the risk of suicidality with antidepressants compared to placebo
in adults beyond age 24; there was a reduction with antidepressants compared to
placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents
with MDD, obsessive compulsive disorder (OCD) or other psychiatric disorders
included a total of 24 short-term trials of nine 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 vs. 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 patients treated) are provided in Table 2. TABLE 2: Suicidality per 1,000 Patients TreatedAge
RangeDrug-Placebo
Difference in Number of Cases of Suicidality per 1,000 Patients
TreatedIncreases Compared to
Placebo< 1814 additional cases18 to 245 additional casesDecreases Compared to
Placebo25 to 641 fewer case> 656 fewer
casesNo 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 (5.13)].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
only for major depressive disorder and obsessive compulsive disorder. Safety and
effectiveness of fluoxetine and olanzapine in combination in patients less than
18 years of age have not been established.

5.2 Serotonin Syndrome Or Neuroleptic Malignant Syndrome (Nms)-Like Reactions

The
development of a potentially life threatening serotonin syndrome or neuroleptic
malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs
alone, including fluoxetine treatment, but particularly with concomitant use of
serotonergic drugs (including triptans) with drugs which impair metabolism of
serotonin (including MAOIs), or with antipsychotics or other dopamine
antagonists. Serotonin syndrome symptoms may include mental status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can
resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
rigidity, autonomic instability with possible rapid fluctuation of vital signs
and mental status changes. Patients should be monitored for the emergence of
serotonin syndrome or NMS-like signs and symptoms.  
The concomitant use of fluoxetine with MAOIs intended to treat depression is
contraindicated [see Contraindications
(4) and Drug Interactions
(7.1)].  
If concomitant treatment of fluoxetine with a 5-hydroxytryptamine receptor
agonist (triptan) is clinically warranted, careful observation of the patient is
advised, particularly during treatment initiation and dose increases [see Drug Interactions
(7.4)]. 
The concomitant use of fluoxetine with serotonin precursors (such as tryptophan)
is not recommended [see Drug Interactions
(7.3)]. 
Treatment with fluoxetine and any concomitant serotonergic or antidopaminergic
agents, including antipsychotics, should be discontinued immediately if the
above reactions occur and supportive symptomatic treatment should be initiated.

5.3 Allergic Reactions And Rash

In U.S. fluoxetine clinical trials as of May 8, 1995, 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, two 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.

5.4 Screening Patients For Bipolar Disorder And Monitoring For Mania/Hypomania

A major depressive episode may be the initial presentation of
bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a 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 U.S. 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 U.S. 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 U.S. placebo-controlled
clinical trials for bulimia. In all U.S. fluoxetine clinical trials as of May 8,
1995, 0.7% of 10,782 patients reported mania/hypomania [see
Use in
Specific Populations (8.4)].

5.5 Seizures

In U.S. 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 U.S.
placebo-controlled clinical trials for either OCD or bulimia. In all U.S.
fluoxetine clinical trials as of May 8, 1995, 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.

5.6 Altered Appetite And Weight

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

5.7 Abnormal Bleeding

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding
reactions. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs,
warfarin and other anticoagulants 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
(7.6)].

5.8 Hyponatremia

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.

5.9 Anxiety And Insomnia

In U.S. 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 U.S. 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 U.S. 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 U.S. 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].

5.10 Use In Patients With Concomitant Illness

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.CardiovascularFluoxetine has not been evaluated or used to any appreciable
extent in patients with a recent history of myocardial infarction or unstable
heart disease. Patients with these diagnoses were systematically excluded from
clinical studies during the product’s premarket testing. However, the
electrocardiograms of 312 patients who received fluoxetine in double-blind
trials were retrospectively evaluated; no conduction abnormalities that resulted
in heart block were observed. The mean heart rate was reduced by approximately 3
beats/min.Glycemic ControlIn patients with diabetes, fluoxetine may alter glycemic control.
Hypoglycemia has occurred during therapy with fluoxetine and hyperglycemia has
developed following discontinuation of the drug. As is true with many other
types of medication when taken concurrently by patients with diabetes, insulin
and/or oral hypoglycemic, dosage may need to be adjusted when therapy with
fluoxetine is instituted or discontinued.

5.11 Potential For Cognitive And Motor Impairment

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.

5.12 Long Elimination Half-Life

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)].

5.13 Discontinuation Of Treatment

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 physician may continue
decreasing the dose but at a more gradual rate. Plasma fluoxetine and
norfluoxetine concentration decrease gradually at the conclusion of therapy
which may minimize the risk of discontinuation symptoms with this drug.

5.14 Fluoxetine And Olanzapine In Combination

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

6 Adverse Reactions

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

6.1 Clinical Trials Experience

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 had been administered to 10,782 patients with
various diagnoses in U.S. clinical trials as of May 8, 1995. In addition, there
have been 425 patients administered fluoxetine in panic clinical trials. Adverse
reactions were recorded by clinical investigators using descriptive terminology
of their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse reactions without
first grouping similar types of reactions into a limited (i.e., reduced) number
of standardized reaction categories. In the tables and tabulations that follow, COSTART Dictionary terminology has
been used to classify reported adverse reactions. 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. It is important to
emphasize that reactions reported during therapy were not necessarily caused by
it. The prescriber should be aware that the figures in the tables and tabulations
cannot be used to predict the incidence of side effects in the course of usual
medical practice where patient characteristics and other factors differ from
those that prevailed in the clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses and investigators. The cited figures,
however, do provide the prescribing physician with some basis for estimating the
relative contribution of drug and nondrug factors to the side effect incidence
rate in the population studied. Incidence in Major Depressive Disorder, OCD, Bulimia
and Panic Disorder Placebo-Controlled Clinical Trials (excluding data from
extensions of trials)Table 3 enumerates the most common treatment-emergent adverse
reactions associated with the use of fluoxetine (incidence of at least 5% for
fluoxetine and at least twice that for placebo within at least one of the
indications) for the treatment of major depressive disorder, OCD and bulimia in
U.S. controlled clinical trials and panic disorder in U.S. plus non-U.S.
controlled trials. Table 5 enumerates treatment-emergent adverse reactions that
occurred in 2% or more patients treated with fluoxetine and with incidence
greater than placebo who participated in U.S. major depressive disorder, OCD and
bulimia controlled clinical trials and U.S. plus non-U.S. panic disorder
controlled clinical trials. Table 4 provides combined data for the pool of
studies that are provided separately by indication in Table 3. TABLE 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in
Major Depressive Disorder, OCD, Bulimia and Panic Disorder Placebo-Controlled
Clinical Trials*†Percentage
of Patients Reporting EventMajor
Depressive DisorderOCDBulimiaPanic
DisorderBody
System/Adverse ReactionFluoxetine (N=1,728)Placebo(N=975)Fluoxetine(N=266)Placebo(N=89)Fluoxetine(N=450)Placebo(N=267)Fluoxetine(N=425)Placebo(N=342)Body as a
WholeAsthenia95151121977Flu syndrome341078355Cardiovascular
SystemVasodilatation325--211--Digestive
SystemNausea21926132911127Diarrhea12818138694Anorexia11217108441Dry mouth1071239644Dyspepsia7510410662Nervous
SystemInsomnia16928223313107Anxiety12714715962Nervousness149141511586Somnolence13617713552Tremor1039113131Libido decreased3--1125112Abnormal dreams11525311Respiratory
SystemPharyngitis3311910533Sinusitis14526423Yawn----7--11--1--Skin and
AppendagesSweating837--8322Rash43634422Urogenital
SystemImpotence‡2------7--1--Abnormal ejaculation‡----7--7--21*Incidence less than 1%†Includes U.S. data for major depressive disorder, OCD, bulimia and panic
disorder clinical trials, plus non-U.S. data for panic disorder clinical trials.‡Denominator used was for males only (N = 690 fluoxetine major depressive
disorder; N = 410 placebo major depressive disorder; N = 116 fluoxetine OCD; N =
43 placebo OCD; N = 4 fluoxetine bulimia; N = 1 placebo bulimia; N = 162
fluoxetine panic; N = 121 placebo panic). TABLE 4: Treatment-Emergent Adverse Reactions: Incidence in Major
Depressive Disorder, OCD, Bulimia and Panic Disorder Placebo-Controlled Clinical
Trials*†Percentage
of Patients Reporting EventMajor
Depressive Disorder, OCD, Bulimia and Panic Disorder CombinedBody
System/Adverse ReactionFluoxetine(N
= 2,869)Placebo(N =
1,673)Body as a
WholeHeadache2119Asthenia116Flu syndrome54Fever21Cardiovascular
SystemVasodilatation21Digestive
SystemNausea229Diarrhea117Anorexia103Dry mouth96Dyspepsia84Constipation54Flatulence32Vomiting32Metabolic and
Nutritional DisordersWeight loss21Nervous
SystemInsomnia1910Nervousness138Anxiety126Somnolence125Dizziness96Tremor92Libido decreased41Thinking abnormal21Respiratory
SystemYawn3--Skin and
AppendagesSweating73Rash43Pruritus32Special
SensesAbnormal vision21*Incidence less than 1%.†Includes U.S. data for major depressive disorder, OCD, bulimia and panic
disorder clinical trials, plus non-U.S. data for panic disorder clinical trials.Associated with Discontinuation in Major Depressive
Disorder, OCD, Bulimia and Panic Disorder Placebo-Controlled Clinical Trials
(excluding data from extensions of trials)Table 5 lists the adverse reactions associated with
discontinuation of fluoxetine treatment (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 major depressive disorder,
OCD, bulimia and panic disorder clinical trials, plus non-U.S. panic disorder
clinical trials. TABLE 5: Most Common Adverse Reactions Associated with Discontinuation
in Major Depressive Disorder, OCD, Bulimia and Panic Disorder Placebo-Controlled
Clinical Trials*Major
Depressive Disorder, OCD, Bulimia and Panic Disorder Combined (N =
1,533)Major Depressive
Disorder (N = 392)OCD (N =
266)Bulimia (N =
450)Panic Disorder (N
= 425)Anxiety (1%)--Anxiety (2%)--Anxiety (2%)------Insomnia (2%)----Nervousness (1%)----Nervousness (1%)----Rash (1%)----*Includes U.S. major depressive disorder, OCD, bulimia and panic disorder
clinical trials, plus non-U.S. panic disorder clinical trials.Other Adverse Reactions in Pediatric Patients
(children and adolescents)Treatment-emergent adverse reactions were collected in 322
pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall
profile of adverse reactions was generally similar to that seen in adult
studies, as shown in Tables 4 and 5. However, the following adverse reactions
(excluding those which appear in the body or footnotes of Tables 4 and 5 and
those for which the COSTART terms were uninformative or misleading) were
reported at an incidence of at least 2% for fluoxetine and greater than placebo:
thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary
frequency and menorrhagia. The most common adverse reaction (incidence at least 1% for fluoxetine and
greater than placebo) associated with discontinuation in three pediatric
placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190
placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for
placebo-treated). In these clinical trials, only a primary reaction associated
with discontinuation was collected. Male and Female Sexual Dysfunction with SSRIsAlthough changes in sexual desire, sexual performance and sexual
satisfaction often occur as manifestations of a psychiatric disorder, they may
also be a consequence of pharmacologic treatment. In particular, some evidence
suggests that SSRIs can cause such untoward sexual experiences. Reliable
estimates of the incidence and severity of untoward experiences involving sexual
desire, performance and satisfaction are difficult to obtain, however, in part
because patients and physicians may be reluctant to discuss them. Accordingly,
estimates of the incidence of untoward sexual experience and performance, cited
in product labeling, are likely to underestimate their actual incidence. In
patients enrolled in U.S. major depressive disorder, OCD and bulimia
placebo-controlled clinical trials, decreased libido was the only sexual side
effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine
of orgasmic dysfunction, including anorgasmia. There are no adequate and well controlled studies examining sexual
dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction
associated with the use of SSRIs, physicians should routinely inquire about such
possible side effects.

6.2 Other Reactions

Following is a list of treatment-emergent adverse reactions
reported by patients treated with fluoxetine in clinical trials. This listing is
not intended to include reactions (1) already listed in previous tables or
elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so
general as to be uninformative, (4) which were not considered to have
significant clinical implications, or (5) which occurred at a rate equal to or
less than placebo. Reactions are classified by body system using the following definitions:
frequent adverse reactions are those occurring in at least 1/100 patients;
infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients;
rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole:Frequent: chills; Infrequent:
suicide attempt; Rare: acute abdominal syndrome,
photosensitivity reaction. Cardiovascular
System:Frequent: palpitation; Infrequent: arrhythmia. Digestive System:Infrequent: dysphagia, gastritis, gastroenteritis, melena,
stomach ulcer; Rare: bloody diarrhea, duodenal ulcer,
esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic
ulcer, stomach ulcer hemorrhage. Hemic and Lymphatic
System:Infrequent: ecchymosis; Rare: petechia, purpura. Nervous System: Frequent: emotional lability; Infrequent: akathisia, ataxia, buccoglossal syndrome,
euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. Respiratory System: Rare: larynx edema. Skin and Appendages: Rare: purpuric rash. Special Senses: Frequent: taste perversion; Infrequent: mydriasis.

6.3 Post-Marketing Experience

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 difficult 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
fibrillation1,
cataract, cerebrovascular accident1, cholestatic jaundice,
dyskinesia (including, for example, a case of buccal-lingual-masticatory
syndrome with involuntary tongue protrusion reported to develop in a 77 year old
female after 5 weeks of fluoxetine therapy and which completely resolved over
the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis,
erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia,
heart arrest1, hepatic
failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic
anemia, kidney failure, movement disorders developing in patients with risk
factors including drugs associated with such reactions and worsening of
preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary
embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson Syndrome,
thrombocytopenia1,
thrombocytopenic purpura, ventricular tachycardia (including Torsades de pointes
type arrhythmias), and vaginal bleeding, and violent behaviors1. 1These terms represent serious adverse events, but do not meet the
definition for adverse drug reactions. They are included here because of their
seriousness.

7 Drug Interactions

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.

7.1 Monoamine Oxidase Inhibitors (Maoi)

There have been reports of serious, sometimes fatal, reactions (including
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid
fluctuations of vital signs and mental status changes that include extreme
agitation progressing to delirium and coma) in patients receiving fluoxetine in
combination with a monoamine oxidase inhibitor (MAOI) and in patients who have
recently discontinued fluoxetine and are then started on an MAOI. Some cases
presented with features resembling neuroleptic malignant syndrome. Therefore,
fluoxetine should not be used in combination with an MAOI, or within a minimum
of 14 days of discontinuing therapy with an MAOI [see Contraindications
(4)]. Since fluoxetine and its major metabolite have very long
elimination half-lives, at least 5 weeks perhaps longer, especially if
fluoxetine has been prescribed chronically and/or at higher doses should be
allowed after stopping fluoxetine before starting an MAOI [see Clinical
Pharmacology (12.3)].

7.2 Cns Acting Drugs

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)].

7.3 Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine, and
the potential for serotonin syndrome, caution is advised when fluoxetine is
coadministered with other drugs that may affect the serotonergic
neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a
reversible nonselective MAOI), lithium, tramadol or St. John’s Wort [see Warnings and
Precautions (5.2)]. The concomitant use of fluoxetine with SNRIs,
SSRIs or tryptophan is not recommended [see Drug Interactions
(7.4), (7.5)].

7.4 Triptans

There have been rare post-marketing reports of serotonin syndrome with use of an
SSRI and a triptan. If concomitant treatment of fluoxetine with a triptan is
clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases [see Warnings and
Precautions (5.2) and Drug Interactions
(7.3)].

7.5 Tryptophan

Five patients receiving fluoxetine in combination with tryptophan experienced
adverse reactions, including agitation, restlessness and gastrointestinal
distress. The concomitant use with tryptophan is not recommended [see Warnings and
Precautions (5.2) and Drug Interactions
(7.3)].

7.6 Drugs That Interfere With Hemostasis (E.G., Nsaids, Aspirin, Warfarin)

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 [seeWarnings and
Precautions (5.2) and Drug Interactions
(7.3)].

7.7 Electroconvulsive Therapy (Ect)

There are no clinical studies establishing the benefit of the combined use of
ECT and fluoxetine. There have been rare reports of prolonged seizures in
patients on fluoxetine receiving ECT treatment.

7.8 Potential For Other Drugs To Affect Fluoxetine

Drugs Tightly Bound to Plasma ProteinsBecause fluoxetine is tightly bound to plasma protein, adverse
effects may result from displacement of protein bound fluoxetine by other
tightly-bound drugs [see C1inical
Pharmacology (12.3)].

7.9 Potential For Fluoxetine To Affect Other Drugs

PimozideConcomitant use in patients taking pimozide is contraindicated.
Clinical studies of pimozide with other antidepressants demonstrate an increase
in drug interaction or QTc prolongation. While a specific
study with pimozide and fluoxetine has not been conducted, the potential for
drug interactions or QTc prolongation warrants
restricting the concurrent use of pimozide and fluoxetine [see Contraindications
(4)].ThioridazineThioridazine should not be administered with fluoxetine or within
a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications
(4)].In a study of 19 healthy male subjects, which included 6 slow and 13 rapid
hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced
a 2.4-fold higher Cmax and a 4.5-fold higher AUC for
thioridazine in the slow hydroxylators compared with the rapid hydroxylators.
The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6
isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6,
such as certain SSRIs, including fluoxetine, will produce elevated plasma levels
of thioridazine. Thioridazine administration produces a dose related prolongation of the
QTc interval, which is associated with serious
ventricular arrhythmias, such as Torsades de pointes type arrhythmias and sudden
death. This risk is expected to increase with fluoxetine-induced inhibition of
thioridazine metabolism. Drugs Metabolized by CYP2D6Fluoxetine inhibits the activity of CYP2D6, and may make
individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer.
Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6,
including certain antidepressants (e.g., TCAs), antipsychotics (e.g.,
phenothiazines and most atypicals) and antiarrhythmics (e.g., propafenone,
flecainide and others) should be approached with caution. Therapy with
medications that are predominantly metabolized by the CYP2D6 system and that
have a relatively narrow therapeutic index (see list below) should be initiated
at the low end of the dose range if a patient is receiving fluoxetine
concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing
requirements resemble those of poor metabolizers. If fluoxetine is added to the
treatment regimen of a patient already receiving a drug metabolized by CYP2D6,
the need for decreased dose of the original medication should be considered.
Drugs with a narrow therapeutic index represent the greatest concern (e.g.,
flecainide, propafenone, vinblastine and TCAs). Due to the risk of serious
ventricular arrhythmias and sudden death potentially associated with elevated
plasma levels of thioridazine, thioridazine should not be administered with
fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued
[see Contraindications
(4)].Tricyclic Antidepressants (TCAs)In two studies, previously stable plasma levels of imipramine and
desipramine have increased greater than 2- to 10-fold when fluoxetine has been
administered in combination. This influence may persist for 3 weeks or longer
after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced
and plasma TCA concentrations may need to be monitored temporarily when
fluoxetine is coadministered or has been recently discontinued [see C1inical
Pharmacology (12.3)].BenzodiazapinesThe half-life of concurrently administered diazepam may be
prolonged in some patients [see C1inical
Pharmacology (12.3)]. Coadministration of alprazolam and
fluoxetine has resulted in increased alprazolam plasma concentrations and in
further psychomotor performance decrement due to increased alprazolam
levels.AntipsychoticsSome clinical data suggests a possible pharmacodynamic and/or
pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood
levels of haloperidol and clozapine has been observed in patients receiving
concomitant fluoxetine [see Contraindications
(4)].AnticonvulsantsPatients on stable doses of phenytoin and carbamazepine have
developed elevated plasma anticonvulsant concentrations and clinical
anticonvulsant toxicity following initiation of concomitant fluoxetine
treatment.LithiumThere have been reports of both increased and decreased lithium
levels when lithium was used concomitantly with fluoxetine. Cases of lithium
toxicity and increased serotonergic effects have been reported. Lithium levels
should be monitored when these drugs are administered concomitantly. Drugs Tightly Bound to Plasma ProteinsBecause fluoxetine is tightly bound to plasma protein, the
administration of fluoxetine to a patient taking another drug that is tightly
bound to protein (e.g., Coumadin®, digitoxin) may cause a
shift in plasma concentrations potentially resulting in an adverse effect [see C1inical
Pharmacology (12.3)].Drugs Metabolized by CYP3A4In an in vivo interaction study
involving coadministration of fluoxetine with single doses of terfenadine (a
CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred
with concomitant fluoxetine.Additionally, in vitro studies have shown
ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times
more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism
of several substrates for this enzyme, including astemizole, cisapride and
midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4
activity is not likely to be of clinical significance. OlanzapineFluoxetine (60 mg single dose or 60 mg daily dose for 8 days)
causes a small (mean 16%) increase in the maximum concentration of olanzapine
and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the
impact of this factor is small in comparison to the overall variability between
individuals, and therefore dose modification is not routinely recommended. When using fluoxetine and olanzapine and in combination,
also refer to the Drug Interactions section of the package insert for
Symbyax®.

8 Use In Specific Populations

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

8.1 Pregnancy

Teratogenic EffectsPregnancy Category CIn embryo-fetal development studies in rats and rabbits, there
was no evidence of teratogenicity following administration of up to 12.5 and 15
mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a
mg/m2 basis) throughout organogenesis. However, in rat
reproduction studies, an increase in stillborn pups, a decrease in pup weight
and an increase in pup deaths during the first 7 days postpartum occurred
following maternal exposure to 12 mg/kg/day [1.5 times the maximum recommended
human dose (MRHD) on a mg/m2 basis] during gestation or
7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis)
during gestation and lactation. There was no evidence of developmental
neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day
during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6
times the MRHD on a mg/m2 basis). Fluoxetine should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus. Treatment of Pregnant Women during the Third
TrimesterNeonates exposed to fluoxetine, SNRIs or SSRIs, late in the third
trimester have developed complications requiring prolonged hospitalization,
respiratory support and tube feeding. Such complications can arise immediately
upon delivery. Reported clinical findings have included respiratory distress,
cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor,
jitteriness, irritability and constant crying. These features are consistent
with either a direct toxic effect of SNRIs and SSRIs or, possibly, a drug
discontinuation syndrome. It should be noted that, in some cases, the clinical
picture is consistent with serotonin syndrome. Infants exposed to SSRIs in late pregnancy may have an increased risk for
persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2
per 1,000 live births in the general population and is associated with
substantial neonatal morbidity and mortality. In a retrospective case control
study of 377 women whose infants were born with PPHN and 836 women whose infants
were born healthy, the risk for developing PPHN was approximately 6-fold higher
for infants exposed to SSRIs after the 20th week of
gestation compared to infants who had not been exposed to antidepressants during
pregnancy. There is currently no corroborative evidence regarding the risk for
PPHN following exposure to SSRIs in pregnancy; this is the first study that has
investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of
PPHN risk. When treating pregnant women with fluoxetine during the third trimester, the
physician should carefully consider both the potential risks and potential
benefits of treatment. Physicians should note that in a prospective longitudinal
study of 201 women with a history of major depression who were euthymic at the
beginning of pregnancy, women who discontinued antidepressant medication during
pregnancy were more likely to experience a relapse of major depression than
women who continued antidepressant medication. The physician may consider tapering fluoxetine in the third trimester.

8.2 Labor And Delivery

The effect of fluoxetine on labor and delivery in humans is unknown. However,
because fluoxetine crosses the placenta and because of the possibility that
fluoxetine may have adverse effects on the newborn, fluoxetine should be used
during labor and delivery only if the potential benefit justifies the potential
risk to the fetus.

8.3 Nursing Mothers

Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not
recommended. In one breast-milk sample, the concentration of fluoxetine plus
norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295
ng/mL. No adverse effects on the infant were reported. In another case, an
infant nursed by a mother on fluoxetine developed crying, sleep disturbance,
vomiting and watery stools. The infant’s plasma drug levels were 340 ng/mL of
fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

8.4 Pediatric Use

The efficacy of fluoxetine for the treatment of major depressive
disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials
with 315 pediatric outpatients ages 8 to <≤ 18 [see Clinical Studies
(14.1)].The efficacy of fluoxetine for the treatment of OCD was demonstrated in one
13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7
to < 18 [see Clinical Studies
(14.2)]. The safety and effectiveness in pediatric patients < 8 years of age in
major depressive disorder and < 7 years of age in OCD have not been
established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6
to < 18) with major depressive disorder or OCD [see Clinical
Pharmacology (12.3)].The acute adverse reaction profiles observed in the three studies (N = 418
randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar
to that observed in adult studies with fluoxetine. The longer term adverse
reaction profile observed in the 19-week major depressive disorder study (N =
219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to
that observed in adult trials with fluoxetine [see Adverse
Reactions (6.1)].Manic reaction, including mania and hypomania, was reported in six (one
mania, five hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0
out of 190 (0%) placebo-treated patients. Mania/hypomania led to the
discontinuation of four (1.8%) fluoxetine-treated patients from the acute phases
of the three studies combined. Consequently, regular monitoring for the
occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association
with the use of fluoxetine in children and adolescent patients. After 19 weeks
of treatment in a clinical trial, pediatric subjects treated with fluoxetine
gained an average of 1.1 cm less in height and 1.1 kg less in weight than
subjects treated with placebo. In addition, fluoxetine treatment was associated
with a decrease in alkaline phosphatase levels. The safety of fluoxetine
treatment for pediatric patients has not been systematically assessed for
chronic treatment longer than several months in duration. In particular, there
are no studies that directly evaluate the longer term effects of fluoxetine on
the growth, development and maturation of children and adolescent patients.
Therefore, height and weight should be monitored periodically in pediatric
patients receiving fluoxetine [see Warnings and
Precautions (5.6)].Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box
Warning and Warnings
and Precautions (5.1)]. Anyone considering the use of
fluoxetine in a child or adolescent must balance the potential risks with the
clinical need. Significant toxicity, including myotoxicity, long-term neurobehavioral and
reproductive toxicity and impaired bone development, has been observed following
exposure of juvenile animals to fluoxetine. Some of these effects occurred at
clinically relevant exposures. In a study in which fluoxetine (3, 10 or 30 mg/kg) was orally administered to
young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and
female sexual development was delayed at all doses, and growth (body weight
gain, femur length) was decreased during the dosing period in animals receiving
the highest dose. At the end of the treatment period, serum levels of creatine
kinase (marker of muscle damage) were increased at the intermediate and high
doses, and abnormal muscle and reproductive organ histopathology (skeletal
muscle degeneration and necrosis, testicular degeneration and necrosis,
epididymal vacuolation and hypospermia) was observed at the high dose. When
animals were evaluated after a recovery period (up to 11 weeks after cessation
of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and
learning deficit at the high dose) and reproductive functional impairment
(decreased mating at all doses and impaired fertility at the high dose) were
seen; in addition, testicular and epididymal microscopic lesions and decreased
sperm concentrations were found in the high dose group, indicating that the
reproductive organ effects seen at the end of treatment were irreversible. The
reversibility of fluoxetine-induced muscle damage was not assessed. Adverse
effects similar to those observed in rats treated with fluoxetine during the
juvenile period have not been reported after administration of fluoxetine to
adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving
the low, intermediate and high dose in this study were approximately 0.1 to 0.2,
1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric
patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat
exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8,
1 to 8, and 3 to 20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice
treated with fluoxetine during the juvenile period. When mice were treated with
fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of
age, bone formation was reduced resulting in decreased bone mineral content and
density. These doses did not affect overall growth (body weight gain or femoral
length). The doses administered to juvenile mice in this study are approximately
0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m2) basis.In another mouse study, administration of fluoxetine (10 mg/kg
intraperitoneal) during early postnatal development (Postnatal Days 4 to 21)
produced abnormal emotional behaviors (decreased exploratory behavior in
elevated plus-maze, increase shock avoidance latency) in adulthood (12 weeks of
age). The dose used in this study is approximately equal to the pediatric MRD on
a mg/m2 basis. Because of the early dosing period in this
study, the significance of these findings to the approved pediatric use in
humans is uncertain. Safety and effectiveness of fluoxetine and olanzapine in combination in
patients less than 18 years of age have not been established.

8.5 Geriatric Use

U.S. 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 (5.8)].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.

8.6 Hepatic Impairment

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its
active metabolite, norfluoxetine, were decreased, thus increasing the
elimination half-lives of these substances. A lower or less frequent dose of
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)].

9 Drug Abuse And Dependence

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9.3 Dependence

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, physicians 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).

10 Overdosage

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10.1 Human Experience

Worldwide exposure to fluoxetine hydrochloride is estimated to be
over 38 million patients (circa 1999). Of the 1,578 cases of overdose involving
fluoxetine hydrochloride, alone or with other drugs, reported from this
population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34
resulted in a fatal outcome, 378 completely recovered and 15 patients
experienced sequelae after overdosage, including abnormal accommodation,
abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction,
vertigo, tremor, elevated blood pressure, impotence, movement disorder and
hypomania. The remaining 206 patients had an unknown outcome. The most common
signs and symptoms associated with nonfatal overdosage were seizures,
somnolence, nausea, tachycardia and vomiting. The largest known ingestion of
fluoxetine hydrochloride in adult patients was 8 grams in a patient who took
fluoxetine alone and who subsequently recovered. However, in an adult patient
who took fluoxetine alone, an ingestion as low as 520 mg has been associated
with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of
overdose involving fluoxetine alone or in combination with other drugs. Six
patients died, 127 patients completely recovered, one patient experienced renal
failure and 22 patients had an unknown outcome. One of the six fatalities was a
9 year old boy who had a history of OCD, Tourette’s syndrome with tics,
attention deficit disorder and fetal alcohol syndrome. He had been receiving 100
mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate
and promethazine. Mixed-drug ingestion or other methods of suicide complicated
all six overdoses in children that resulted in fatalities. The largest ingestion
in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single
or multiple drugs) include coma, delirium, ECG abnormalities (such as QT
interval prolongation and ventricular tachycardia, including Torsades de pointes
type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like
reactions, pyrexia, stupor and syncope.

10.2 Animal Experience

Studies in animals do not provide precise or necessarily valid
information about the treatment of human overdose. However, animal experiments
can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248
mg/kg, respectively. Acute high oral doses produced hyperirritability and
convulsions in several animal species. Among six dogs purposely overdosed with oral fluoxetine, five experienced
grand mal seizures. Seizures stopped immediately upon the bolus intravenous
administration of a standard veterinary dose of diazepam. In this short-term
study, the lowest plasma concentration at which a seizure occurred was only
twice the maximum plasma concentration seen in humans taking 80 mg/day,
chronically. In a separate single-dose study, the ECG of dogs given high doses did not
reveal prolongation of the PR, QRS or QT intervals. Tachycardia and an increase
in blood pressure were observed. Consequently, the value of the ECG in
predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily
be monitored in cases of human overdose [see Overdosage
(10.3)].

10.3 Management Of Overdose

Treatment should consist of those general measures employed in
the management of overdosage with any drug effective in the treatment of major
depressive disorder. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac
rhythm and vital signs. General supportive and symptomatic measures are also
recommended. Induction of emesis is not recommended. Gastric lavage with a
large-bore orogastric tube with appropriate airway protection, if needed, may be
indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of
distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange
transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine
are known. A specific caution involves patients who are taking or have recently taken
fluoxetine and might ingest excessive quantities of a TCA. In such a case,
accumulation of the parent tricyclic and/or an active metabolite may increase
the possibility of clinically significant sequelae and extend the time needed
for close medical observation [see Drug Interactions
(7. 9)].Based on experience in animals, which may not be relevant to humans,
fluoxetine-induced seizures that fail to remit spontaneously may respond to
diazepam. In managing overdosage, consider the possibility of multiple drug
involvement. The physician should consider contacting a poison control center
for additional information on the treatment of any overdose. Telephone numbers
for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).For specific information about overdosage with olanzapine and fluoxetine in
combination, refer to the Overdosage section of the Symbyax® package insert.

11 Description

Fluoxetine is a selective serotonin reuptake inhibitor for oral administration.
It is also marketed for the treatment of premenstrual dysphoric disorder
(Sarafem®, fluoxetine hydrochloride). It is designated
(±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the molecular
formula of C17H18F3NO·HCl. Its molecular weight is 345.79. The structural formula
is: Fluoxetine hydrochloride, USP is a white to off-white crystalline solid with
a solubility of 14 mg/mL in water.Each capsule contains fluoxetine hydrochloride equivalent to 10 mg, 20 mg or
40 mg of fluoxetine. The capsules also contain colloidal silicon dioxide,
magnesium stearate, pregelatinized starch and sodium lauryl sulfate. In
addition, each of the empty gelatin capsules contains gelatin, sodium lauryl
sulfate and titanium dioxide and the following colorant agents: 10 mg – FD&C
Red No. 40; the 20 mg – FD&C Blue No. 1 and FD&C Red No. 40; and the 40
mg – FD&C Blue No. 1 and FD&C Red No. 3.The imprinting ink contains the following: black iron oxide, D&C Yellow
No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2
Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac
glaze.

12 Clinical Pharmacology

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12.1 Mechanism Of Action

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

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Systemic BioavailabilityIn man, following a single oral 40 mg dose, peak plasma
concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8
hours. The capsule, oral solution and weekly capsule dosage forms of fluoxetine are
bioequivalent. Food does not appear to affect the systemic bioavailability of
fluoxetine, although it may delay its absorption by 1 to 2 hours, which is
probably not clinically significant. Thus, fluoxetine may be administered with
or without food.Protein BindingOver the concentration range from 200 to 1000 ng/mL,
approximately 94.5% of fluoxetine is bound in vitro
to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other
highly protein bound drugs has not been fully evaluated, but may be important.
EnantiomersFluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine
enantiomers. In animal models, both enantiomers are specific and potent
serotonin uptake inhibitors with essentially equivalent pharmacologic activity.
The S-fluoxetine enantiomer is eliminated more slowly
and is the predominant enantiomer present in plasma at steady-state. MetabolismFluoxetine is extensively metabolized in the liver to
norfluoxetine and a number of other unidentified metabolites. The only
identified active metabolite, norfluoxetine, is formed by demethylation of
fluoxetine. In animal models, S-norfluoxetine is a
potent and selective inhibitor of serotonin uptake and has activity essentially
equivalent to R- or S-fluoxetine. R-norfluoxetine is
significantly less potent than the parent drug in the inhibition of serotonin
uptake. The primary route of elimination appears to be hepatic metabolism to
inactive metabolites excreted by the kidney. Variability in MetabolismA subset (about 7%) of the population has reduced activity of the
drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are
referred to as “poor metabolizers” of drugs such as debrisoquin,
dextromethorphan and the TCAs. In a study involving labeled and unlabeled
enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher
concentrations of S-fluoxetine. Consequently,
concentrations of S-norfluoxetine at steady state
were lower. The metabolism of R-fluoxetine in these
poor metabolizers appears normal. When compared with normal metabolizers, the
total sum at steady-state of the plasma concentrations of the four active
enantiomers was not significantly greater among poor metabolizers. Thus, the net
pharmacodynamic activities were essentially the same. Alternative, nonsaturable
pathways (non-2D6) also contribute to the metabolism of fluoxetine. This
explains how fluoxetine achieves a steady-state concentration rather than
increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds
including TCAs and other selective serotonin reuptake inhibitors (SSRIs),
involves the CYP2D6 system, concomitant therapy with drugs also metabolized by
this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions
(7.9)].Accumulation and Slow EliminationThe relatively slow elimination of fluoxetine (elimination
half-life of 1 to 3 days after acute administration and 4 to 6 days after
chronic administration) and its active metabolite, norfluoxetine (elimination
half-life of 4 to 16 days after acute and chronic administration), leads to
significant accumulation of these active species in chronic use and delayed
attainment of steady-state, even when a fixed dose is used [see Warnings and
Precautions (5.12)]. After 30 days of dosing at 40 mg/day,
plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and
norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma
concentrations of fluoxetine were higher than those predicted by single-dose
studies, because fluoxetine’s metabolism is not proportional to dose.
Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean
terminal half-life after a single dose was 8.6 days and after multiple dosing
was 9.3 days. Steady-state levels after prolonged dosing are similar to levels
seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that,
even when dosing is stopped, active drug substance will persist in the body for
weeks (primarily depending on individual patient characteristics, previous
dosing regimen and length of previous therapy at discontinuation). This is of
potential consequence when drug discontinuation is required or when drugs are
prescribed that might interact with fluoxetine and norfluoxetine following the
discontinuation of fluoxetine.

12.4 Specific Populations

Liver DiseaseAs might be predicted from its primary site of metabolism, liver
impairment can affect the elimination of fluoxetine. The elimination half-life
of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6
days compared with the range of 2 to 3 days seen in subjects without liver
disease; norfluoxetine elimination was also delayed, with a mean duration of 12
days for cirrhotic patients compared with the range of 7 to 9 days in normal
subjects. This suggests that the use of fluoxetine in patients with liver
disease must be approached with caution. If fluoxetine is administered to
patients with liver disease, a lower or less frequent dose should be used [see Dosage and
Administration (2.7), Use in Specific
Populations (8.6)].Renal DiseaseIn depressed patients on dialysis (N = 12), fluoxetine
administered as 20 mg once daily for 2 months produced steady-state fluoxetine
and norfluoxetine plasma concentrations comparable with those seen in patients
with normal renal function. While the possibility exists that renally excreted
metabolites of fluoxetine may accumulate to higher levels in patients with
severe renal dysfunction, use of a lower or less frequent dose is not routinely
necessary in renally impaired patients. Geriatric PharmacokineticsThe disposition of single doses of fluoxetine in healthy elderly
subjects (> 65 years of age) did not differ significantly from that in
younger normal subjects. However, given the long half-life and nonlinear
disposition of the drug, a single-dose study is not adequate to rule out the
possibility of altered pharmacokinetics in the elderly, particularly if they
have systemic illness or are receiving multiple drugs for concomitant diseases.
The effects of age upon the metabolism of fluoxetine have been investigated in
260 elderly but otherwise healthy depressed patients (> 60 years of age) who
received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine
plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual
age-associated pattern of adverse reactions was observed in those elderly
patients.Pediatric Pharmacokinetics (children and
adolescents)Fluoxetine pharmacokinetics were evaluated in 21 pediatric
patients (ten children ages 6 to < 13, 11 adolescents ages 13 to < 18)
diagnosed with major depressive disorder or obsessive compulsive disorder (OCD).
Fluoxetine 20 mg/day was administered for up to 62 days. The average
steady-state concentrations of fluoxetine in these children were 2-fold higher
than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine
steady-state concentrations in these children were 1.5-fold higher than in
adolescents (195 and 113 ng/mL, respectively). These differences can be almost
entirely explained by differences in weight. No gender-associated difference in
fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and
norfluoxetine plasma concentrations were observed in another study in 94
pediatric patients (ages 8 to < 18) diagnosed with major depressive disorder.
Higher average steady-state fluoxetine and norfluoxetine concentrations were
observed in children relative to adults; however, these concentrations were
within the range of concentrations observed in the adult population. As in
adults, fluoxetine and norfluoxetine accumulated extensively following multiple
oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of
daily dosing.

13 Nonclinical Toxicology

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13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenicityThe dietary administration of fluoxetine to rats and mice for 2
years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and
0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a
mg/m2 basis], produced no evidence of
carcinogenicity.MutagenicityFluoxetine and norfluoxetine have been shown to have no genotoxic
effects based on the following assays: bacterial mutation assay, DNA repair
assay in cultured rat hepatocytes, mouse lymphoma assay and in vivo sister chromatid exchange assay in Chinese hamster
bone marrow cells. Impairment of FertilityTwo fertility studies conducted in adult rats at doses of up to
7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on
fertility. However, adverse effects on fertility were seen when juvenile rats
were treated with fluoxetine [see Use in
Specific Populations (8.4)].

13.2 Animal Toxicology And/Or Pharmacology

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.

14 Clinical Studies

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

14.1 Major Depressive Disorder

Daily DosingAdultThe efficacy of fluoxetine was studied in 5- and 6-week
placebo-controlled trials with depressed adult and geriatric outpatients (> 18
years of age) whose diagnoses corresponded most closely to the DSM-III
(currently DSM-IV) category of major depressive disorder. Fluoxetine was shown
to be significantly more effective than placebo as measured by the Hamilton
Depression Rating Scale (HAM-D). Fluoxetine was also significantly more
effective than placebo on the HAM-D subscores for depressed mood, sleep
disturbance and the anxiety subfactor. Two 6-week controlled studies (N = 671, randomized) comparing fluoxetine 20
mg and placebo have shown fluoxetine 20 mg daily to be effective in the
treatment of elderly patients (> 60 years of age) with major depressive
disorder. In these studies, fluoxetine produced a significantly higher rate of
response and remission as defined, respectively, by a 50% decrease in the HAM-D
score and a total endpoint HAM-D score of < 8. Fluoxetine was well tolerated and
the rate of treatment discontinuations due to adverse reactions did not differ
between fluoxetine (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded
(modified HAMD-17 score of < 7 during each of the last 3 weeks of open-label
treatment and absence of major depressive disorder by DSM-III-R criteria) by the
end of an initial 12-week open-treatment phase on fluoxetine 20 mg/day. These
patients (N = 298) were randomized to continuation on double-blind fluoxetine 20
mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly
lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major
depressive disorder for 2 weeks or a modified HAMD-17 score of >14 for 3 weeks)
was observed for patients taking fluoxetine compared with those on placebo.
Pediatric (children and adolescents)The efficacy of fluoxetine 20 mg/day in children and adolescents
(N = 315 randomized; 170 children ages 8 to < 13, 145 adolescents ages 13 to < 18) was studied in two 8- to 9-week placebo-controlled clinical trials in
depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R
or DSM-IV category of major depressive disorder. In both studies independently, fluoxetine produced a statistically
significantly greater mean change on the Childhood Depression Rating
Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo.
Subgroup analyses on the CDRS-R total score did not suggest any differential
responsiveness on the basis of age or gender.

14.2 Obsessive Compulsive Disorder

AdultThe effectiveness of fluoxetine for the treatment of obsessive
compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel
group studies (Studies 1 and 2) of adult outpatients who received fixed
fluoxetine doses of 20, 40 or 60 mg/day (on a once-a-day schedule, in the
morning) or placebo. Patients in both studies had moderate to severe OCD
(DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive
Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving
fluoxetine experienced mean reductions of approximately 4 to 6 units on the
YBOCS total score, compared with a 1-unit reduction for placebo patients. In
Study 2, patients receiving fluoxetine experienced mean reductions of
approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit
reduction for placebo patients. While there was no indication of a dose-response
relationship for effectiveness in Study 1, a dose-response relationship was
observed in Study 2, with numerically better responses in the two higher dose
groups. The following table provides the outcome classification by treatment
group on the Clinical Global Impression (CGI) improvement scale for Studies 1
and 2 combined:TABLE 6Outcome
Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD
Studies FluoxetineOutcome ClassificationPlacebo20 mg40 mg60 mgWorse8%0%0%0%No Change64%41%33%29%Minimally Improved17%23%28%24%Much Improved8%28%27%28%Very Much Improved3%8%12%19%Exploratory analyses for age and gender effects on outcome did not suggest
any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents)In one 13-week clinical trial in pediatric patients (N = 103
randomized; 75 children ages 7 to < 13, 28 adolescents ages 13 to < 18)
with OCD (DSM-IV), patients received fluoxetine 10 mg/day for 2 weeks, followed
by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60
mg/day on the basis of clinical response and tolerability. Fluoxetine produced a
statistically significantly greater mean change from baseline to endpoint than
did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale
(CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness
on the basis of age or gender.

14.3 Bulimia Nervosa

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 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 three 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 three 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 vs. 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 three
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 physician 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.

14.4 Panic Disorder

The effectiveness of fluoxetine in the treatment of panic
disorder was demonstrated in two 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 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% vs. 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 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% vs. 44%, respectively.

16 How Supplied/Storage And Handling

Enter section text here

16.1 How Supplied

Fluoxetine Capsules, USP are available containing fluoxetine
hydrochloride, USP equivalent to 10 mg, 20 mg or 40 mg of fluoxetine.The 20 mg capsule is a hard-shell gelatin capsule with a light turquoise blue
opaque cap and a flesh opaque body axially printed with MYLAN over 4220 in black ink on both
the cap and the body. The capsule is filled with white to off-white powder. They
are available as follows:
Bottles of 30NDC 54868-4537-0Bottles of 60NDC 54868-4537-1Bottles of 90NDC 54868-4537-3Bottles of 100NDC 54868-4537-2Bottles of 240NDC 54868-4537-4The 40 mg capsule is a hard-shell gelatin capsule with a light blue opaque
cap and a white opaque body axially printed with MYLAN
over 4350 in black ink on both the cap and the body. The
capsule is filled with white to off-white powder. They are available as follows:Bottles of 30NDC 54868-4562-0Bottles of 90NDC 54868-4562-1

16.2 Storage And Handling

Store at 20° to 25°C (68° to 77°F). [See USP
Controlled Room Temperature.]Protect from light.Dispense in a tight, light-resistant container as defined in the USP using a
child-resistant closure.PHARMACIST: Dispense a Medication Guide with each
prescription.

17 Patient Counseling Information

See the FDA-Approved 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®.

17.1 General Information

Healthcare providers should instruct their patients to read the
Medication Guide before starting therapy with fluoxetine capsules and to reread
it each time the prescription is renewed.Healthcare providers should inform patients, their families and their
caregivers about the benefits and risks associated with treatment with
fluoxetine and should counsel them in its appropriate use. Healthcare providers
should instruct patients, their families and their caregivers to read the
Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. Patients
should be advised of the following issues and asked to alert their healthcare
provider if these occur while taking fluoxetine.When using fluoxetine and olanzapine in combination, also
refer to the Medication Guide for Symbyax®.

17.2 Clinical Worsening And Suicide Risk

Patients, their families and their caregivers should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression and
suicidal ideation, especially early during antidepressant treatment and when the
dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day to day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s
prescriber or health professional, especially if they are severe, abrupt in
onset or were not part of the patient’s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and
behavior and indicate a need for very close monitoring and possibly changes in
the medication [see Box Warning and Warnings
and Precautions (5.1)].

17.3 Serotonin Syndrome Or Neuroleptic Malignant Syndrome (Nms)-Like Reactions

Patients should be cautioned about the risk of serotonin syndrome
or NMS-like reactions with the concomitant use of fluoxetine and triptans,
tramadol or other serotonergic agents [see Warnings and
Precautions (5.2) and Drug Interactions
(7.3)].Patients should be advised of the signs and symptoms associated with
serotonin syndrome or NMS-like reactions that may include mental status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can
resemble neuroleptic malignant syndrome, in which the symptoms may include
hyperthermia, muscle rigidity, autonomic instability with possible rapid
fluctuation of vital signs and mental status changes. Patients should be
cautioned to seek medical care immediately if they experience these symptoms.

17.4 Allergic Reactions And Rash

Patients should be advised to notify their physician if they develop a rash or
hives [see Warnings and
Precautions (5.3)]. Patients should also be advised of the
signs and symptoms associated with a severe allergic reaction, including
swelling of the face, eyes or mouth, or have trouble breathing. Patients should
be cautioned to seek medical care immediately if they experience these symptoms.

17.5 Abnormal Bleeding

Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs,
aspirin, warfarin or other drugs that affect coagulation since combined use of
psychotropic drugs that interfere with serotonin reuptake and these agents have
been associated with an increased risk of bleeding [see
Warnings and
Precautions (5.7) and Drug Interactions
(7.6)]. Patients should be advised to call their doctor if
they experience any increased or unusual bruising or bleeding while taking
fluoxetine.

17.6 Hyponatremia

Patients should be advised that hyponatremia has been reported as a result of
treatment with SNRIs and SSRIs, including fluoxetine. Signs and symptoms of
hyponatremia include headache, difficulty concentrating, memory impairment,
confusion, weakness and unsteadiness, which may lead to falls. More severe
and/or acute cases have been associated with hallucination, syncope, seizure,
coma, respiratory arrest and death [see Warnings and
Precautions (5.8)].

17.7 Potential For Cognitive And Motor Impairment

Fluoxetine may impair judgment, thinking or motor skills. Patients should be
advised to avoid driving a car or operating hazardous machinery until they are
reasonably certain that their performance is not affected [see Warnings and
Precautions (5.11)].

17.8 Use Of Concomitant Medications

Patients should be advised to inform their physician if they are taking or plan
to take, any prescription medication, including Symbyax®,
Sarafem® or over-the-counter drugs, including herbal
supplements or alcohol. Patients should also be advised to inform their
physicians if they plan to discontinue any medications they are taking while on
fluoxetine.

17.9 Discontinuation Of Treatment

Patients should be advised to take fluoxetine exactly as prescribed, and to
continue taking fluoxetine as prescribed even after their symptoms improve.
Patients should be advised that they should not alter their dosing regimen, or
stop taking fluoxetine without consulting their physician [see Warnings and
Precautions (5.13)]. Patients should be advised to consult
with their healthcare provider if their symptoms do not improve with fluoxetine.

17.10 Use In Specific Populations

PregnancyPatients should be advised to notify their physician if they
become pregnant or intend to become pregnant during therapy. Fluoxetine should
be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus [see Use in Specific
Populations (8.1)]. Nursing MothersPatients should be advised to notify their physician if they
intend to breast-feed an infant during therapy. Because fluoxetine is excreted
in human milk, nursing while taking fluoxetine is not recommended [see Use in
Specific Populations (8.3)].Pediatric UseFluoxetine is approved for use in pediatric patients with MDD and
OCD [see Box Warning and Warnings
and Precautions (5.1)]. Limited evidence is available
concerning the longer term effects of fluoxetine on the development and
maturation of children and adolescent patients. Height and weight should be
monitored periodically in pediatric patients receiving fluoxetine. Safety and
effectiveness of fluoxetine and olanzapine in combination in patients less than
18 years of age have not been established [see Warnings and
Precautions (5.6) and Use in
Specific Populations (8.4)].

Other

Coumadin® is a trademark of Bristol-Myers
Squibb.Symbyax® is a trademark of Eli
Lilly.Sarafem® is a trademark of Eli Lilly.Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED JULY 2009FLUX:R23mpbmtRelabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK       74146

Spl Medguide

  • MEDICATION GUIDE FLUOXETINE CAPSULESRead 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
  • Doctor about your medical condition or treatment. Talk with your doctor or
  • Pharmacist if there is something you do not understand or you want to learn more
  • About fluoxetine. What is the most important information I should know about
  • Fluoxetine? Antidepressant medicines, depression and other serious
  • Mental illnesses and suicidal thoughts or actions:Talk to your or your family member’s, healthcare provider
  • Aboutall risks and benefits of treatment with antidepressant medicinesall treatment choices for depression or other serious mental
  • IllnessAntidepressant medicines may increase suicidal thoughts or
  • Actions in some children, teenagers and young adults within the first few months
  • Of treatment.Depression and other serious mental illnesses are the most
  • Important causes of suicidal thoughts and actions. Some people may have a
  • Particularly high risk of having suicidal thoughts or actions. These
  • Include people who have (or have a family history of) bipolar illness (also
  • Called manic-depressive illness) or suicidal thoughts or actions.How can I watch for and try to prevent suicidal thoughts
  • And actions in myself or a family member?Pay close attention to any changes, especially sudden changes, in mood,
  • Behaviors, thoughts or feelings. This is very important when an antidepressant
  • Medicine is started or when the dose is changed.Call the healthcare provider right away to report new or sudden changes in
  • Mood, behavior, thoughts or feelings.Keep all follow-up visits with the healthcare provider as scheduled. Call
  • The healthcare provider between visits as needed, especially if you have
  • Concerns about symptoms.Call a healthcare provider right away if you or your family
  • Member has any of the following symptoms, especially if they are new, worse or
  • Worry you:thoughts about suicide or dyingattempts to commit suicidenew or worse depressionnew or worse anxietyfeeling very agitated or restlesspanic attackstrouble sleeping (insomnia)new or worse irritabilityacting aggressive, being angry or violentacting on dangerous impulsesan extreme increase in activity and talking (mania)or other unusual changes in behavior or moodWhat else do I need to know about antidepressant
  • Medicines?Never stop an antidepressant medicine without first talking
  • To a healthcare provider. Stopping an antidepressant medicine suddenly
  • Can cause other symptoms.Antidepressants are medicines used to treat depression and
  • Other illnesses. It is important to discuss all the risks of treating
  • Depression and also the risks of not treating it. Patients and their families or
  • Other caregivers should discuss all treatment choices with the healthcare
  • Provider, not just the use of antidepressants.Antidepressant medicines have other side effects.
  • Talk to the healthcare provider about the side effects of the medicine
  • Prescribed for you or your family member.Antidepressant medicines can interact with other
  • Medicines. Know all of the medicines that you or your family member
  • Takes. Keep a list of all medicines to show the healthcare provider. Do not
  • Start new medicines without first checking with your healthcare provider.Not all antidepressant medicines prescribed for children
  • Are FDA approved for use in children. Talk to your child’s healthcare
  • Provider for more information. What is fluoxetine? Fluoxetine is a prescription medicine used:for short and long-term treatment of depression in adults and children over
  • The age of 8.for short and long-term treatment of obsessive compulsive disorder (OCD) in
  • Adults and children over the age of 7.for short and long-term treatment of bulimia nervosa in adults.for short-term treatment of panic disorder, with or without agoraphobia, in
  • Adults.with the medicine olanzapine (Zyprexa®†), for the
  • Short-term treatment of episodes of depression that happen with bipolar I
  • Disorder.It is not known if fluoxetine and olanzapine (Zyprexa®†) taken together is safe and works in children under 18 years
  • Of age. The symptoms of depression (major depressive disorder and bipolar I disorder)
  • Include decreased mood, decreased interest, increased guilty feelings, decreased
  • Energy, decreased concentration, changes in appetite and suicidal thoughts or
  • Behavior. With treatment, some of your symptoms of depression may improve. OCD is an anxiety disorder and is characterized by recurrent, unwanted
  • Thoughts (obsessions) and/or repetitive behaviors (compulsions). With treatment,
  • Some of your symptoms of OCD may improve. Panic disorder is an anxiety disorder that includes panic attacks, which are
  • Sudden feelings of terror for no reason. You may also have physical symptoms,
  • Such as; fast heartbeat, chest pain, breathing difficulty, dizziness. With
  • Treatment, some of your symptoms of panic disorder may improve. Bulimia nervosa, involves periods of overeating followed by purging (e.g.
  • Vomiting, excessive laxative use). With treatment, some of your symptoms of
  • Bulimia nervosa may improve. If you do not think you are getting better, call your doctor. Who should not take fluoxetine?Do not take fluoxetine if you take a Monoamine Oxidase Inhibitor (MAOI) or
  • If you stopped taking an MAOI in the last 2 weeks.Do not take an MAOI within 5 weeks of stopping
  • Fluoxetine. People who take fluoxetine close in time to an MAOI can have
  • Serious and life threatening side effects, with symptoms including:
  • High fevercontinued muscle spasms that you can not controlrigid muscleschanges in heart rate and blood pressure that happen fastconfusionunconsciousnessAsk your doctor or pharmacist if you are not sure if your
  • Medicine is an MAOI.Do not take fluoxetine if you take Mellaril®†
  • (thioridazine). Do not take Mellaril®†within 5 weeks of stopping fluoxetine. Mellaril®†  can cause
  • Serious heart rhythm problems and you could die suddenly.Do not take fluoxetine if you take the antipsychotic medicine pimozide
  • (Orap®†). What should I tell my doctor before taking fluoxetine?
  • Fluoxetine may not be right for you. Before starting fluoxetine, tell your
  • Doctor about all your medical conditions, including if you have or had any of
  • The following:seizures (convulsions) bipolar disorder (mania) are pregnant or plan to become pregnant. It is not known if fluoxetine will
  • Harm your unborn baby. are breast-feeding or plan to breast-feed. Fluoxetine can pass into your
  • Breast milk and may harm your baby. You should not breast-feed while taking
  • Fluoxetine. Talk to your doctor about the best way to feed your baby if you take
  • Fluoxetine. Tell your doctor about all the medicines that you
  • Take, including prescription and non-prescription medicines, vitamins and
  • Herbal supplements. Fluoxetine and some medicines may interact with each other
  • And may not work as well, or cause possible serious side effects. Your doctor
  • Can tell you if it is safe to take fluoxetine with your other medicines. Do not
  • Start or stop any medicine while taking fluoxetine without talking to your
  • Doctor first. If you take fluoxetine, you should not take any other
  • Medicines that contain fluoxetine hydrochloride:Symbyax®†Sarafem®†Prozac Weekly®†You could take too much medicine (overdose).How should I take fluoxetine? Take fluoxetine exactly as prescribed. Your doctor may need to change
  • (adjust) the dose of fluoxetine until it is right for you. If you miss a dose of fluoxetine, 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 at the
  • Same time.To prevent serious side effects, do not stop taking
  • Fluoxetine suddenly. If you need to stop taking fluoxetine, your doctor can tell
  • You how to safely stop taking it. If you take too much fluoxetine, call your doctor or poison
  • Control center right away, or get emergency treatment.Fluoxetine can be taken with or without food. Fluoxetine is usually taken once a day, depending on how your doctor
  • Prescribes your medicine.If you do not think you are getting better or have any concerns about your
  • Condition while taking fluoxetine, call your doctor. What should I avoid while taking fluoxetine?Fluoxetine can cause sleepiness and 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 affects
  • You.What are the possible side effects of fluoxetine?
  • Fluoxetine may be associated with the following serious
  • Risks:Serotonin Syndrome: This is a condition that can be
  • Life threatening. Call your doctor right away if you become severely ill and
  • Have some or all of these symptoms:
  • Agitation hallucinations problems with coordination racing heart beatover-active reflexesfever nausea, vomiting and diarrhea Severe allergic reactions: Tell your doctor right
  • Away if you get red itchy welts (hives) or, a rash alone or with fever and joint
  • Pain, while taking fluoxetine. Call your doctor right away if you become
  • Severely ill and have some or all of these symptoms:
  • Swelling of your face, eyes or mouth trouble breathingAbnormal bleeding: Tell your doctor if you notice
  • Any increased or unusual bruising or bleeding while taking fluoxetine,
  • Especially if you take one of these medicines:
  • The blood thinner warfarin (Coumadin®†, Jantoven®†) a non-steroidal anti-inflammatory drug (NSAID)aspirin Mania: You may have a high mood, become extremely
  • Irritable, have too much energy, feel pressure to keep talking or have a
  • Decreased need for sleep. SeizuresLoss of appetiteLow salt (sodium) levels in the blood
  • (hyponatremia): Call your doctor right away if you become severely ill
  • And have some or all of these symptoms:
  • Headache feel weak confusion problems concentrating memory problems feel unsteadyCommon possible side effects of fluoxetine include:
  • Abnormal dreams, orgasm problems, decreased appetite, anxiety, weakness,
  • Diarrhea, dry mouth, indigestion, flu, difficulty maintaining an erection for
  • Sexual activity, trouble sleeping, decreased sex drive, feeling sick to your
  • Stomach, nervousness, sore throat, rash, watery nasal discharge, sleepiness,
  • Sweating, tremor (shakes), hot flashes and yawn. Tell your doctor about any side effect that bothers you or that does not go
  • Away. These are not all the possible side effects with fluoxetine. For more
  • Information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You
  • May report side effects to FDA at 1-800-FDA-1088. How should I store fluoxetine capsules? Store fluoxetine capsules at 20° to 25°C (68° to 77°F). [See USP Controlled
  • Room Temperature.]Keep fluoxetine away from light.Keep fluoxetine bottle closed tightly. Keep fluoxetine and all medicines out of the reach of
  • Children. General information about fluoxetineMedicines are sometimes prescribed for purposes other than those listed in a
  • Medication Guide. Do not use fluoxetine for a condition for which it was not
  • Prescribed. Do not give fluoxetine 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 doctor.
  • You can ask your doctor or pharmacist for information about fluoxetine that was
  • Written for healthcare professionals. For more information about fluoxetine call
  • Mylan Pharmaceuticals Inc. at 1-877-446-3769 (1-877-4-INFO-RX). What are the ingredients in fluoxetine capsules? Active ingredients: fluoxetine hydrochloride, USPInactive ingredients: colloidal silicon dioxide,
  • Magnesium stearate, pregelatinized starch and sodium lauryl sulfate. In
  • Addition, each of the empty gelatin capsules contains gelatin, sodium lauryl
  • Sulfate and titanium dioxide and the following colorant agents: 10 mg – FD&C
  • Red No. 40; the 20 mg – FD&C Blue No. 1 and FD&C Red No. 40; and the 40
  • Mg – FD&C Blue No. 1 and FD&C Red No. 3. The imprinting ink contains the
  • Following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue
  • No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40
  • Aluminum Lake, propylene glycol and shellac glaze.† The brand names mentioned in this Medication Guide
  • Are registered trademarks of their respective manufacturers.This Medication Guide has been approved by the U.S. Food and Drug
  • Administration.Mylan Pharmaceuticals Inc.Morgantown, WV 26505JULY 2009MG:FLUX:R1

* Please review the disclaimer below.