FLUOXETINE HYDROCHLORIDE
-
fluoxetine hydrochloride capsule
REMEDYREPACK INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use fluoxetine safely and effectively. See full prescribing information for fluoxetine capsules.
Fluoxetine Capsules, USP for Oral Use
Initial U.S. Approval: 1987
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WARNING: SUICIDALITY AND
ANTIDEPRESSANT DRUGS
See full prescribing information for complete boxed
warning.
Increased risk of
suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder
(MDD) and other psychiatric disorders (5.1).
When using fluoxetine and
olanzapine in combination, also refer to Boxed Warning section of the package
insert for Symbyax. |
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INDICATIONS AND USAGE
|
Fluoxetine capsules are a selective serotonin reuptake inhibitor indicated
for:
- Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult
and pediatric patients aged 8 to 18 years (1.1)
- Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in
adult and pediatric patients aged 7 to 17 years (1.2)
- Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3)
- Acute treatment of Panic Disorder, with or without agoraphobia, in adult
patients (1.4)
Fluoxetine capsules and olanzapine in
combination for:
- Acute treatment of Depressive Episodes Associated with Bipolar I Disorder in
adults (1.5)
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DOSAGE AND ADMINISTRATION
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Indication
| Adult
| Pediatric
|
MDD (2.1)
| 20 mg/day in am (initial dose)
| 10 to 20 mg/day (initial dose)
|
OCD (2.2)
| 20 mg/day in am (initial dose)
| 10 mg/day (initial dose)
|
Bulimia Nervosa (2.3)
| 60 mg/day in am
| -
|
Panic Disorder (2.4)
| 10 mg/day (initial dose)
| -
|
Depressive Episodes Associated
with Bipolar I Disorder (2.5)
| Oral in combination with olanzapine: 5 mg of
oral olanzapine and 20 mg of fluoxetine once daily (initial dose)
| -
|
- Consider tapering the dose of fluoxetine for pregnant women during the third
trimester (2.7)
- A lower or less frequent dosage should be used in patients with hepatic
impairment, the elderly, and for patients with concurrent disease or on multiple
concomitant medications (2.7)
Fluoxetine capsules and
olanzapine in combination:
- Dosage adjustments, if indicated, should be made with the individual
components according to efficacy and tolerability (2.5)
- Fluoxetine monotherapy is not indicated for the treatment of Depressive
Episodes associated with Bipolar I Disorder (2.5)
- Safety of the coadministration of doses above 18 mg olanzapine with 75 mg
fluoxetine has not been evaluated (2.5)
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DOSAGE FORMS AND STRENGTHS
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- Capsules: 10 mg, 20 mg, and 40 mg (3)
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CONTRAINDICATIONS
|
- Do not use with an MAOI or within 14 days of discontinuing an MAOI due to
risk of drug interaction. At least 5 weeks should be allowed after stopping
fluoxetine capsules before treatment with an MAOI (4,
7.1)
- Do not use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.9)
- Do not use with thioridazine due to QTc interval
prolongation or potential for elevated thioridazine plasma levels. Do not use
thioridazine within 5 weeks of discontinuing fluoxetine capsules (4, 7.9)
- When using fluoxetine capsules and olanzapine in combination, also refer to
the Contraindications section of the package insert for Symbyax (4)
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WARNINGS AND PRECAUTIONS
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-
Clinical Worsening and Suicide Risk: Monitor for
clinical worsening and suicidal thinking and behavior (5.1)
-
Serotonin Syndrome or Neuroleptic Malignant Syndrome
(NMS)-like Reactions: Have been reported with fluoxetine. Discontinue
fluoxetine and initiate supportive treatment (5.2)
-
Allergic Reactions and Rash: Discontinue upon
appearance of rash or allergic phenomena (5.3)
-
Activation of Mania/Hypomania: Screen for Bipolar
Disorder and monitor for mania/hypomania (5.4)
-
Seizures: Use cautiously in patients with a
history of seizures or with conditions that potentially lower the seizure
threshold (5.5)
-
Altered Appetite and Weight: Significant weight
loss has occurred (5.6)
-
Abnormal Bleeding: May increase the risk of
bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation
may potentiate the risk of gastrointestinal or other bleeding (5.7)
-
Hyponatremia: Has been reported with fluoxetine
in association with syndrome of inappropriate antidiuretic hormone (SIADH) (5.8)
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Anxiety and Insomnia: May occur (5.9)
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Potential for Cognitive and Motor Impairment: Has
potential to impair judgment, thinking, and motor skills. Use caution when
operating machinery (5.11)
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Long Half-Life: Changes in dose will not be fully
reflected in plasma for several weeks (5.12)
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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 (5.14)
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ADVERSE REACTIONS
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Most common adverse reactions (≥5% and at least twice that for placebo)
associated with:
Major Depressive Disorder, Obsessive Compulsive
Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation,
anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome,
impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash,
sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1)
Fluoxetine and olanzapine in combination -
Also refer to the Adverse Reactions section of the package insert for Symbyax
(6)
To report SUSPECTED ADVERSE REACTIONS, contact
Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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DRUG INTERACTIONS
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-
Monoamine Oxidase Inhibitors (MAOI): Fluoxetine
is contraindicated for use with MAOI’s, or within 14 days of discontinuing an
MAOI due to risk of drug interaction. At least 5 weeks should be allowed after
stopping fluoxetine before starting treatment with an MAOI (4, 7.1)
-
Pimozide: Fluoxetine is contraindicated for use
with pimozide due to risk of drug interaction or QTc
prolongation (4, 7.9)
-
Thioridazine: Fluoxetine is contraindicated for
use with thioridazine due to QTc interval prolongation or
potential for elevated thioridazine plasma levels. Do not use thioridazine
within 5 weeks of discontinuing fluoxetine (4, 7.9)
-
Drugs Metabolized by CYP2D6: Fluoxetine is a
potent inhibitor of CYP2D6 enzyme pathway (7.9)
-
Tricyclic Antidepressants (TCAs): Monitor TCA
levels during coadministration with fluoxetine or when fluoxetine has been
recently discontinued (7.9)
-
CNS Acting Drugs: Caution should be used when
taken in combination with other centrally acting drugs (7.2)
-
Benzodiazepines: Diazepam - increased t½,
alprazolam – further psychomotor performance decrement due to increased levels
(7.9)
-
Antipsycotics: Potential for elevation of
haloperidol and clozapine levels (7.9)
-
Anticonvulsants: Potential for elevated phenytoin
and carbamazepine levels and clinical anticonvulsant toxicity (7.9)
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Serotonergic Drugs: Potential for Serotonin
Syndrome (5.2, 7.3)
-
Triptans: There have been rare postmarketing
reports of Serotonin Syndrome with use of an SSRI and a triptan (5.2, 7.4)
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Tryptophan: Concomitant use with tryptophan is
not recommended (5.2, 7.5)
-
Drugs that Interfere with Hemostasis (e.g., NSAIDs,
Aspirin, Warfarin): May potentiate the risk of bleeding (7.6)
-
Drugs Tightly Bound to Plasma Proteins: May cause
a shift in plasma concentrations (7.8, 7.9)
-
Olanzapine: When used in combination with
fluoxetine, also refer to the Drug Interactions section of the package insert
for Symbyax (7.9)
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USE IN SPECIFIC POPULATIONS
|
-
Pregnancy: Fluoxetine should be used during
pregnancy only if the potential benefit justifies the potential risks to the
fetus (8.1)
-
Nursing Mothers: Breast feeding is not
recommended (8.3)
-
Pediatric Use: Safety and effectiveness of
fluoxetine and olanzapine in combination have not been established in patients
less than 18 years of age (8.4)
-
Hepatic Impairment: Lower or less frequent dosing
may be appropriate in patients with cirrhosis (8.6)
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See 17 for
PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide
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Revised: 12/2010 |
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FULL PRESCRIBING INFORMATION
BOXED WARNING
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
Antidepressants 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.
INDICATIONS & USAGE
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 to 18
years
[see Clinical Studies
(14.1)].
The usefulness of the drug in adult and pediatric
patients receiving fluoxetine for extended periods, should periodically be
re-evaluated
[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 capsules 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 re-evaluate 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 re-evaluate 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 capsules 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 re-evaluate the long-term
usefulness of the drug for the individual patient
[see Dosage and Administration (2.4)].1.5 Fluoxetine Capsules and Olanzapine in
Combination: Depressive Episodes Associated with Bipolar I
Disorder
When using fluoxetine capsules and
olanzapine in combination, also refer to the Clinical Studies section of the
package insert for Symbyax®.
Fluoxetine
capsules and olanzapine
in
combination are indicated for the acute treatment of depressive episodes
associated with Bipolar I Disorder in adult patients.
Fluoxetine
capsules monotherapy is not indicated for the treatment of depressive episodes
associated with Bipolar I Disorder.
DOSAGE & ADMINISTRATION
2.1 Major Depressive Disorder
Initial Treatment
Adult — In 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 1 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
patients — As 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
Treatment — It 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 Dosing — Systematic 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 Treatment
Adult — In the controlled clinical
trials of fluoxetine supporting its effectiveness in the treatment of OCD,
patients were administered fixed daily doses of 20, 40, 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 Treatment —
While 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 capsules 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 Treatment — In the controlled clinical trials of
fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa,
patients were administered fixed daily fluoxetine doses of 20 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
Treatment — Systematic 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 Treatment — In 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 2 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 Treatment — While 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 Capsules and Olanzapine in
Combination: Depressive Episodes Associated with Bipolar I
Disorder
When using fluoxetine capsules 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 to 50 mg and oral olanzapine 5
to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and
fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and
fluoxetine 25 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 capsules and olanzapine versus Symbyax. Dosage adjustments, if
indicated, should be made with the individual components according to efficacy
and tolerability.
Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of Fluoxetine and Olanzapine
For Symbyax (mg/day) | Use in Combination |
Olanzapine (mg/day) | Fluoxetine
(mg/day) |
1
|
3 mg olanzapine/25 mg fluoxetine
| 2.5
| 20
|
6 mg olanzapine/25 mg fluoxetine
| 5
| 20
|
12 mg olanzapine/25 mg fluoxetine
| 10+2.5
| 20
|
6 mg olanzapine/50 mg fluoxetine
| 5
| 40+10
|
12 mg olanzapine/50 mg fluoxetine
| 10+2.5
| 40+10
|
While there is no body of
evidence to answer the question of how long a patient treated with fluoxetine
capsules 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
re-examine the need for continued pharmacotherapy.
Safety of
coadministration of doses above 18 mg olanzapine
with 75 mg fluoxetine has not
been evaluated in clinical studies.
Fluoxetine capsules 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 Trimester —
When 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)].
Geriatrics — A lower or
less frequent dosage should be considered for the elderly
[see Use in Specific Populations
(8.5)].
Hepatic Impairment — As
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 Illness — Patients with
concurrent disease or on multiple concomitant medications may require dosage
adjustments
[see Clinical
Pharmacology (12.4) and Warnings and Precautions
(5.10)].
Fluoxetine Capsules and Olanzapine in Combination — The starting dose of oral
olanzapine 2.5 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,
non-smoking 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 capsules 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)].
DOSAGE FORMS & STRENGTHS
Fluoxetine Capsules USP, 10 mg*
are opaque green
cap/opaque green body, size ‘3’ hard gelatin capsule filled with white to
off-white granular powder and imprinted with ‘E’ on opaque green cap and ‘88’ on
opaque green body with black ink.
Fluoxetine Capsules USP, 20 mg*
are opaque green cap/opaque off white body, size ‘3’ hard
gelatin capsule filled with white to off-white granular powder and imprinted
with ‘E’ on opaque green cap and ‘91’ on opaque off white body with black
ink.
Fluoxetine Capsules USP, 40 mg*
are opaque
green cap/opaque orange body, size ‘2’ hard gelatin capsule filled with white to
off-white granular powder and imprinted with ‘E’ on opaque green cap and ‘92’ on
opaque orange body with black ink.
CONTRAINDICATIONS
When using fluoxetine capsules
and olanzapine in combination, also refer to the Contraindications section of
the package insert for Symbyax.
The use of fluoxetine capsules
are contraindicated with the following:
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 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric
disorders included a total of 295 short-term trials (median duration of 2
months) of 11 antidepressant drugs in over 77,000 patients. There was
considerable variation in risk of suicidality among drugs, but a tendency toward
an increase in the younger patients for almost all drugs studied. There were
differences in absolute risk of suicidality across the different indications,
with the highest incidence in MDD. The risk differences (drug versus placebo),
however, were relatively stable within age strata and across indications. These
risk differences (drug-placebo difference in the number of cases of suicidality
per 1000 patients treated) are provided in Table 2.
Table 2: Suicidality per 1000 Patients Treated
Age Range | Drug-Placebo Difference in Number of
Cases of Suicidality per 1000 Patients Treated |
| Increases Compared to
Placebo
|
greater then 18
| 14 additional cases
|
18-24
| 5 additional cases
|
| Decreases Compared to
Placebo
|
25-64
| 1 fewer case
|
less then65
| 6 fewer
cases
|
No suicides occurred in any of the pediatric
trials. There were suicides in the adult trials, but the number was not
sufficient to reach any conclusion about drug effect on suicide.
It is
unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can
delay the recurrence of depression.
All patients being
treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and
unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic
attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania, and mania, have been reported
in adult and pediatric patients being treated with antidepressants for Major
Depressive Disorder as well as for other indications, both psychiatric and
nonpsychiatric. Although a causal link between the emergence of such symptoms
and either the worsening of depression and/or the emergence of suicidal impulses
has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to
changing the therapeutic regimen, including possibly discontinuing the
medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe,
abrupt in onset, or were not part of the patient’s presenting
symptoms.
If the decision has been made to discontinue treatment,
medication should be tapered, as rapidly as is feasible, but with recognition
that abrupt discontinuation can be associated with certain symptoms
[see Warnings and Precautions
(5.13)].
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, 2 patients are known to have developed a serious
cutaneous systemic illness. In neither patient was there an unequivocal
diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the
other, a severe desquamating syndrome that was considered variously to be a
vasculitis or erythema multiforme. Other patients have had systemic syndromes
suggestive of serum sickness.
Since the introduction of fluoxetine,
systemic reactions, possibly related to vasculitis and including lupus-like
syndrome, have developed in patients with rash. Although these reactions are
rare, they may be serious, involving the lung, kidney, or liver. Death has been
reported to occur in association with these systemic
reactions.
Anaphylactoid reactions, including bronchospasm, angioedema,
laryngospasm, and urticaria alone and in combination, have been
reported.
Pulmonary reactions, including inflammatory processes of
varying histopathology and/or fibrosis, have been reported rarely. These
reactions have occurred with dyspnea as the only preceding
symptom.
Whether these systemic reactions and rash have a common
underlying cause or are due to different etiologies or pathogenic processes is
not known. Furthermore, a specific underlying immunologic basis for these
reactions has not been identified. Upon the appearance of rash or of other
possibly allergic phenomena for which an alternative etiology cannot be
identified, fluoxetine should be discontinued.
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, nonsteroidal anti-inflammatory drugs, warfarin, and other
anti-coagulants may add to this risk. Case reports and epidemiological studies
(case-control and cohort design) have demonstrated an association between use of
drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use
have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages. Patients should be cautioned about the risk of
bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin,
warfarin, or other drugs that affect coagulation
[see Drug Interactions (7.6)].
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.
Cardiovascular — Fluoxetine 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 Control — In 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.
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 1 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 Trials1,2
| Percentage of Patients
Reporting Event |
| Major
Depressive Disorder | OCD | Bulimia | Panic
Disorder |
|
Body System/Adverse Reaction
| Fluoxetine
(N=1728)
| Placebo
(N=975)
| Fluoxetine
(N=266)
| Placebo
(N=89)
| Fluoxetine
(N=450)
| Placebo
(N=267)
| Fluoxetine
(N=425)
| Placebo
(N=342)
|
Body as a Whole
|
|
|
|
|
|
|
|
|
Asthenia
| 9
| 5
| 15
| 11
| 21
| 9
| 7
| 7
|
Flu syndrome
| 3
| 4
| 10
| 7
| 8
| 3
| 5
| 5
|
Cardiovascular System
|
|
|
|
|
|
|
|
|
Vasodilatation
| 3
| 2
| 5
| --
| 2
| 1
| 1
| --
|
Digestive System
|
|
|
|
|
|
|
|
|
Nausea
| 21
| 9
| 26
| 13
| 29
| 11
| 12
| 7
|
Diarrhea
| 12
| 8
| 18
| 13
| 8
| 6
| 9
| 4
|
Anorexia
| 11
| 2
| 17
| 10
| 8
| 4
| 4
| 1
|
Dry mouth
| 10
| 7
| 12
| 3
| 9
| 6
| 4
| 4
|
Dyspepsia
| 7
| 5
| 10
| 4
| 10
| 6
| 6
| 2
|
Nervous System
|
|
|
|
|
|
|
|
|
Insomnia
| 16
| 9
| 28
| 22
| 33
| 13
| 10
| 7
|
Anxiety
| 12
| 7
| 14
| 7
| 15
| 9
| 6
| 2
|
Nervousness
| 14
| 9
| 14
| 15
| 11
| 5
| 8
| 6
|
Somnolence
| 13
| 6
| 17
| 7
| 13
| 5
| 5
| 2
|
Tremor
| 10
| 3
| 9
| 1
| 13
| 1
| 3
| 1
|
Libido decreased
| 3
| --
| 11
| 2
| 5
| 1
| 1
| 2
|
Abnormal dreams
| 1
| 1
| 5
| 2
| 5
| 3
| 1
| 1
|
Respiratory System
|
|
|
|
|
|
|
|
|
Pharyngitis
| 3
| 3
| 11
| 9
| 10
| 5
| 3
| 3
|
Sinusitis
| 1
| 4
| 5
| 2
| 6
| 4
| 2
| 3
|
Yawn
| --
| --
| 7
| --
| 11
| --
| 1
| --
|
Skin and Appendages
|
|
|
|
|
|
|
|
|
Sweating
| 8
| 3
| 7
| --
| 8
| 3
| 2
| 2
|
Rash
| 4
| 3
| 6
| 3
| 4
| 4
| 2
| 2
|
Urogenital System
|
|
|
|
|
|
|
|
|
Impotence3
| 2
| --
| --
| --
| 7
| --
| 1
| --
|
Abnormal ejaculation3
| --
| --
| 7
| --
| 7
| --
| 2
| 1
|
Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major
Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled
Clinical Trials1, 2
| Percentage of Patients
Reporting Event |
| Major Depressive Disorder,
OCD, Bulimia, and Panic Disorder Combined |
|
Body
System/Adverse Reaction
| Fluoxetine
(N=2869)
| Placebo
(N=1673)
|
Body as a Whole
|
|
|
Headache
| 21
| 19
|
Asthenia
| 11
| 6
|
Flu syndrome
| 5
| 4
|
Fever
| 2
| 1
|
Cardiovascular System
|
|
|
Vasodilatation
| 2
| 1
|
Digestive System
|
|
|
Nausea
| 22
| 9
|
Diarrhea
| 11
| 7
|
Anorexia
| 10
| 3
|
Dry mouth
| 9
| 6
|
Dyspepsia
| 8
| 4
|
Constipation
| 5
| 4
|
Flatulence
| 3
| 2
|
Vomiting
| 3
| 2
|
Metabolic and Nutritional
Disorders
|
|
|
Weight loss
| 2
| 1
|
Nervous System
|
|
|
Insomnia
| 19
| 10
|
Nervousness
| 13
| 8
|
Anxiety
| 12
| 6
|
Somnolence
| 12
| 5
|
Dizziness
| 9
| 6
|
Tremor
| 9
| 2
|
Libido decreased
| 4
| 1
|
Thinking abnormal
| 2
| 1
|
Respiratory System
|
|
|
Yawn
| 3
| --
|
Skin and Appendages
|
|
|
Sweating
| 7
| 3
|
Rash
| 4
| 3
|
Pruritus
| 3
| 2
|
Special Senses
|
|
|
Abnormal vision
| 2
| 1
|
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 Trials1
|
Major Depressive
Disorder, OCD, Bulimia, and Panic Disorder Combined
(N=1533)
| 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%)
| --
| --
|
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 3
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 SSRIs — Although 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, greater then 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 Postmarketing 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 fibrillation
1,
cataract, cerebrovascular accident
1, 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 pneumonia
1, epidermal necrolysis, erythema
multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart
arrest
1, 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 pre-existing movement disorders, optic
neuritis, pancreatitis
1, pancytopenia, pulmonary
embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome,
thrombocytopenia
1, thrombocytopenic purpura, ventricular
tachycardia (including torsades de pointes–type arrhythmias), and vaginal
bleeding, and violent behaviors
1.
1 These terms represent serious adverse
events, but do not meet the definition for adverse drug reactions. They are
included here because of their seriousness.
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
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 non-selective 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
postmarketing 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
[see Warnings and Precautions
(5.7)].
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 Proteins
– Because fluoxetine is tightly bound to plasma protein, adverse effects
may result from displacement of protein-bound fluoxetine by other tightly-bound
drugs
[see Clinical Pharmacology
(12.3)].
7.9 Potential for Fluoxetine to affect Other
Drugs
Pimozide — Concomitant use in patients
taking pimozide is contraindicated. Clinical studies of pimozide with other
antidepressants demonstrate an increase in drug interaction or QT
c prolongation. While a specific study with pimozide and
fluoxetine has not been conducted, the potential for drug interactions or
QT
c prolongation warrants restricting the concurrent use
of pimozide and fluoxetine
[see Contraindications (4)].
Thioridazine — Thioridazine 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 C
max 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 QT
c 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 CYP2D6 — Fluoxetine 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
2 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 Clinical Pharmacology (12.3)].
Benzodiazapines — The
half-life of concurrently administered diazepam may be prolonged in some
patients
[see Clinical 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.
Antipsychotics — Some 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)].
Anticonvulsants —
Patients on stable doses of phenytoin and carbamazepine have developed
elevated plasma anticonvulsant concentrations and clinical anticonvulsant
toxicity following initiation of concomitant fluoxetine treatment.
Lithium — There have been
reports of both increased and decreased lithium levels when lithium was used
concomitantly with fluoxetine. Cases of lithium toxicity and increased
serotonergic effects have been reported. Lithium levels should be monitored when
these drugs are administered concomitantly.
Drugs
Tightly Bound to Plasma Proteins — Because
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 Clinical Pharmacology (12.3)].
Drugs Metabolized by CYP3A4 —
In 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.
Olanzapine —
Fluoxetine (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.
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 Effects
Pregnancy Category C — In
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/m
2 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/m
2 basis) during gestation or 7.5
mg/kg/day (0.9 times the MRHD on a mg/m
2 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/m
2 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 Trimester
— Neonates 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 1000 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 six-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 greater then 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 greater then 18
[see Clinical Studies (14.2)].
The safety and effectiveness in pediatric
patients greater then 8 years of age in Major Depressive Disorder and greater then 7 years of age
in OCD have not been established.
Fluoxetine pharmacokinetics were
evaluated in 21 pediatric patients (ages 6 to greater then 18) with Major Depressive
Disorder or OCD
[see Clinical
Pharmacology (12.3)].
The acute adverse reaction profiles
observed in the 3 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 6 (1 mania, 5 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 4 (1.8%) fluoxetine-treated patients from the acute
phases of the 3 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/m
2) 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/m
2 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 less then 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 less then 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)].
DRUG ABUSE AND DEPENDENCE
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).
OVERDOSAGE
10.1 Human Experience
Worldwide exposure to
fluoxetine hydrochloride is estimated to be over 38 million patients (circa
1999). Of the 1578 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 non-fatal 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, 1 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 6 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 6 dogs purposely overdosed with oral fluoxetine, 5
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.
DESCRIPTION
Fluoxetine capsules, USP are a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafemfluoxetine hydrochloride). It is designated (hydrochloride and has the molecular formula of C17H18F3NOHCl. Its molecular weight is 345.79. The structural formula is:
Fluoxetine hydrochloride 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 (32.320 mg (64.7or 40 mg (129.3of fluoxetine. The capsules also contain the following inactive ingredients: pregelatinized starch, colloidal silicon dioxide, FD&C Blue #1, yellow iron oxide, titanium dioxide, sodium lauryl sulphate, and gelatin. In addition 40 mg also contains FD&C Yellow #6. The capsules are printed with edible ink containing black iron oxide and shellac.
CLINICAL PHARMACOLOGY
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 α
1-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 Bioavailability — In 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 and oral solution 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 Binding
— Over the concentration range from 200 to 1000 ng/mL, approximately
94.5% of fluoxetine is bound
in vitro to human serum
proteins, including albumin and α
1-glycoprotein. The
interaction between fluoxetine and other highly protein-bound drugs has not been
fully evaluated, but may be important.
Enantiomers — Fluoxetine is a racemic mixture (50/50) of
R-fluoxetine and
S-fluoxetine enantiomers. In animal models, both
enantiomers are specific and potent serotonin uptake inhibitors with essentially
equivalent pharmacologic activity. The
S-fluoxetine
enantiomer is eliminated more slowly and is the predominant enantiomer present
in plasma at steady state.
Metabolism —
Fluoxetine 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 Metabolism — A
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 4 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 Elimination — The relatively slow elimination of fluoxetine
(elimination half-life of 1 to 3 days after acute administration and 4 to 6 days
after chronic administration) and its active metabolite, norfluoxetine
(elimination half-life of 4 to 16 days after acute and chronic administration),
leads to significant accumulation of these active species in chronic use and
delayed attainment of steady state, even when a fixed dose is used
[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 Disease — As might be predicted from its primary site
of metabolism, liver impairment can affect the elimination of fluoxetine. The
elimination half-life of fluoxetine was prolonged in a study of cirrhotic
patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in
subjects without liver disease; norfluoxetine elimination was also delayed, with
a mean duration of 12 days for cirrhotic patients compared with the range of 7
to 9 days in normal subjects. 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 Disease — In
depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once
daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma
concentrations comparable with those seen in patients with normal renal
function. While the possibility exists that renally excreted metabolites of
fluoxetine may accumulate to higher levels in patients with severe renal
dysfunction, use of a lower or less frequent dose is not routinely necessary in
renally impaired patients.
Geriatric
Pharmacokinetics — The disposition of single doses of fluoxetine in
healthy elderly subjects ( less then 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 (less then 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 (10 children ages 6 to greater then 13, 11 adolescents ages 13 to greater then 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 greater then 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.
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
Carcinogenicity — The 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/m
2 basis], produced no evidence of carcinogenicity.
Mutagenicity — Fluoxetine 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
Fertility — Two 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/m
2 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.
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 Dosing
Adult — The
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 (less then 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 greater then 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 greater then 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 greater then 13, 145 adolescents ages 13 to greater then 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
Adult — The 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 2 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 6: Outcome Classification (%) on CGI Improvement Scale for
Completers in Pool of Two OCD Studies
| Fluoxetine |
Outcome Classification
| Placebo
| 20 mg
| 40 mg
| 60 mg
|
Worse
| 8%
| 0%
| 0%
| 0%
|
No change
| 64%
| 41%
| 33%
| 29%
|
Minimally improved
| 17%
| 23%
| 28%
| 24%
|
Much improved
| 8%
| 28%
| 27%
| 28%
|
Very much improved
| 3%
| 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 greater then 13, 28 adolescents ages 13 to greater then 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 3 studies had moderate to severe bulimia with median
binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9
per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was
statistically significantly superior to placebo in reducing the number of
binge-eating and vomiting episodes per week. The statistically significantly
superior effect of 60 mg versus placebo was present as early as Week 1 and
persisted throughout each study. The fluoxetine-related reduction in bulimic
episodes appeared to be independent of baseline depression as assessed by the
Hamilton Depression Rating Scale. In each of these 3 studies, the treatment
effect, as measured by differences between fluoxetine 60 mg and placebo on
median reduction from baseline in frequency of bulimic behaviors at endpoint,
ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per
week for vomiting. The size of the effect was related to baseline frequency,
with greater reductions seen in patients with higher baseline frequencies.
Although some patients achieved freedom from binge-eating and purging as a
result of treatment, for the majority, the benefit was a partial reduction in
the frequency of binge-eating and purging.
In a longer-term trial, 150
patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had
responded during a single-blind, 8-week acute treatment phase with fluoxetine 60
mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for
up to 52 weeks of observation for relapse. Response during the single-blind
phase was defined by having achieved at least a 50% decrease in vomiting
frequency compared with baseline. Relapse during the double-blind phase was
defined as a persistent return to baseline vomiting frequency or 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 2
double-blind, randomized, placebo-controlled, multicenter studies of adult
outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or
without agoraphobia.
Study 1 (N=180 randomized) was a 12-week
flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week,
after which patients were dosed in the range of 20 to 60 mg/day on the basis of
clinical response and tolerability. A statistically significantly greater
percentage of fluoxetine-treated patients were free from panic attacks at
endpoint than placebo-treated patients, 42% versus 28%,
respectively.
Study 2 (N=214 randomized) was a 12-week flexible-dose
study. Fluoxetine was initiated at 10 mg/day for the first week, after which
patients were dosed in a range of 20 to 60 mg/day on the basis of clinical
response and tolerability. A statistically significantly greater percentage of
fluoxetine-treated patients were free from panic attacks at endpoint than
placebo-treated patients, 62% versus 44%, respectively.
HOW SUPPLIED
16.1 How Supplied
Fluoxetine
Capsules USP, 10 mg* are opaque green cap/opaque green body, size ‘3’
hard gelatin capsule filled with white to off-white granular powder and
imprinted with ‘E’ on opaque green cap and ‘88’ on opaque green body with black
ink.
Bottles of 100 NDC
65862-192-01
Bottles of 500 NDC
65862-192-05
Bottles of 1000 NDC
65862-192-99
Fluoxetine Capsules USP,
20 mg* are opaque green cap/opaque off white body, size ‘3’ hard
gelatin capsule filled with white to off-white granular powder and imprinted
with ‘E’ on opaque green cap and ‘91’ on opaque off white body with black
ink.
Bottles of 100 NDC
65862-193-01
Bottles of 500 NDC
65862-193-05
Bottles of 1000 NDC
65862-193-99
Fluoxetine Capsules USP,
40 mg* are opaque green cap/opaque orange body, size ‘2’ hard
gelatin capsule filled with white to off-white granular powder and imprinted
with ‘E’ on opaque green cap and ‘92’ on opaque orange body with black
ink.
Bottles of 30 NDC
65862-194-30
Bottles of 100 NDC
65862-194-01
Bottles of 500 NDC
65862-194-05
Bottles of 1000 NDC
65862-194-99
*Fluoxetine base equivalent.
16.2 Storage and Handling
Store at 20° to 25°C (68° to 77°F); excursions permitted to
15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Preserve in
tight, light-resistant containers.
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 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
Pregnancy — Patients 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 Mothers —
Patients 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 Use — Fluoxetine
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)].
MEDICATION GUIDE
Fluoxetine Capsules, USP
Read the Medication
Guide that comes with fluoxetine capsules before you start taking them 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 capsules.
What is the most important information I should know about fluoxetine
capsules?
Antidepressant medicines, depression
and other serious mental illnesses, and suicidal thoughts or
actions:
Talk to your, or your family member’s,
healthcare provider about:
- all risks and benefits of treatment with antidepressant medicines
- all treatment choices for depression or other serious mental
illness
-
Antidepressant 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 dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling very agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- or other unusual changes in behavior or mood
What 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 are fluoxetine
capsules?
Fluoxetine capsules are 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 capsules 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 capsules?
- Do not take fluoxetine capsules 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
capsules. People who take fluoxetine capsules close in time to an MAOI
can have serious and life-threatening side effects, with symptoms including:
- high fever
- continued muscle spasms that you can not control
- rigid muscles
- changes in heart rate and blood pressure that happen fast
- confusion
- unconsciousness
Ask your doctor or pharmacist if you
are not sure if your medicine is an MAOI.
- Do not take fluoxetine capsules if you take Mellaril
(thioridazine). Do not take Mellaril within 5 weeks of stopping
fluoxetine capsules. Mellaril can cause serious heart
rhythm problems and you could die suddenly.
- Do not take fluoxetine capsules if you take the antipsychotic medicine
pimozide (Orap).
What should I tell my doctor before taking
fluoxetine capsules?
Fluoxetine capsules may not be right for
you. Before starting fluoxetine capsules, 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
capsules 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 capsules. Talk to your doctor about the best way to feed your baby if
you take fluoxetine capsules.
Tell your doctor
about all the medicines that you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. Fluoxetine
capsules and some medicines may interact with each other and may not work as
well, or cause possible serious side effects. Your doctor can tell you if it is
safe to take fluoxetine capsules with your other medicines. Do not start or stop
any medicine while taking fluoxetine capsules without talking to your doctor
first.
If you take fluoxetine capsules, you should not
take any other medicines that contain fluoxetine hydrochloride:
You could take too much
medicine (overdose).
How should I take fluoxetine
capsules?
- Take fluoxetine capsules exactly as prescribed. Your doctor may need to
change (adjust) the dose of fluoxetine capsules until it is right for you.
- If you miss a dose of fluoxetine capsules, take the missed dose as soon as
you remember. If it is almost time for the next dose, skip the missed dose and
take your next dose at the regular time. Do not take two doses of fluoxetine
capsules at the same time.
-
To prevent serious side effects, do not stop taking
fluoxetine capsules suddenly. If you need to stop taking
fluoxetine capsules, your doctor can tell you how to safely stop taking
them.
-
If you take too much fluoxetine capsules, call your doctor
or poison control center right away, or get emergency treatment.
- Fluoxetine capsules can be taken with or without food.
- Fluoxetine capsules are 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 capsules, call your
doctor.
What should I avoid while taking
fluoxetine capsules?
- Fluoxetine capsules 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
capsules affect you.
What are the possible side
effects of fluoxetine capsules?
Fluoxetine
capsules 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 beat
- over-active reflexes
- fever
- 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 capsules. 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 breathing
-
Abnormal bleeding: Tell your doctor if you notice
any increased or unusual bruising or bleeding while taking fluoxetine capsules,
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.
-
Seizures
-
Loss of appetite
-
Low 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 unsteady
Common possible side
effects of fluoxetine capsules 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 capsules. 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); excursions permitted
to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
- Keep fluoxetine capsules away from light.
- Keep fluoxetine capsules bottle closed tightly.
Keep fluoxetine capsules and all medicines out of the reach of
children.
General information about fluoxetine
capsules
Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. Do not use fluoxetine capsules for a
condition for which it was not prescribed. Do not give fluoxetine capsules to
other people, even if they have the same condition. They 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
capsules that was written for healthcare professionals. For more information
about fluoxetine capsules call 1-866-850-2876.
What are
the ingredients in fluoxetine capsules?
Active
ingredient: fluoxetine hydrochloride
Inactive
ingredients: pregelatinized starch, colloidal silicon dioxide, FD and C
Blue No 1, yellow iron oxide, titanium dioxide, sodium lauryl sulphate, and
gelatin. In addition 40 mg also contains FD and C Yellow No 6. The capsules are
printed with edible ink containing black iron oxide and shellac.
Symbyax and Sarafem are registered trademarks of Eli Lilly and
Company.
Mellaril
is a registered trademark of
Novartis AG Corporation.
Orap
is a registered
trademark of Teva Pharmaceuticals USA.
Coumadin is a
registered trademark of Bristol Myers Squibb.
Jantoven
is a registered trademark of Upsher-Smith Laboratories
Inc.
Zyprexa
is a registered trademark of Eli Lilly
and Company.
This Medication Guide has been approved by the U.S. Food and
Drug Administration.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION
DRUG: FLUOXETINE HYDROCHLORIDE
GENERIC: FLUOXETINE HYDROCHLORIDE
DOSAGE: CAPSULE
ADMINSTRATION: ORAL
NDC: 49349-479-02
STRENGTH:10 mg
COLOR: green
SHAPE: CAPSULE
SCORE: No score
SIZE: 16 mm
IMPRINT: E;88
QTY: 30
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
DRUG: FLUOXETINE HYDROCHLORIDE
GENERIC: FLUOXETINE HYDROCHLORIDE
DOSAGE: CAPSULE
ADMINSTRATION: ORAL
NDC: 49349-479-20
STRENGTH:10 mg
COLOR: green
SHAPE: CAPSULE
SCORE: No score
SIZE: 16 mm
IMPRINT: E;88
QTY: 100
FLUOXETINE HYDROCHLORIDE
fluoxetine hydrochloride
capsule |
|
|
|
|
|
Revised: 12/2010REMEDYREPACK INC.