Prozac CA PM

PRODUCT MONOGRAPH
INCLUDING PATIENT MEDICATION INFORMATION
Pr PROZAC ®
fluoxetine hydrochloride
Capsules, 10 mg and 20 mg (equivalent to Fluoxetine), Oral
Antidepressant / Antiobsessional / Antibulimic
© Eli Lilly Canada Inc. Date of Initial Authorization:

Exchange Tower DEC 31,1989
130 King Street West, Suite 900
PO Box 73 Date of Revision:
Toronto, Ontario July 13, 2021
M5X 1B1
1-888-545-5972
www.lilly.ca
Submission Control Number: 249549
PROZAC (fluoxetine hydrochloride) Page 1 of 51

RECENT MAJOR LABEL CHANGES
7 Warnings and Precautions 07/2021

7 Warnings and Precautions, 7.1.1 Pregnant Women 07/2021
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES.............................................................................................. 2
TABLE OF CONTENTS ................................................................................................................ 2
PART I: HEALTH PROFESSIONAL INFORMATION....................................................................... 4
1 INDICATIONS................................................................................................................. 4
1.1 Pediatrics ............................................................................................................. 4
1.2 Geriatrics ............................................................................................................. 4
2 CONTRAINDICATIONS ................................................................................................... 4
4 DOSAGE AND ADMINISTRATION .................................................................................. 5
4.1 Dosing Considerations.......................................................................................... 5
4.2 Recommended Dose and Dosage Adjustment...................................................... 6
4.4 Administration ..................................................................................................... 7
4.5 Missed Dose......................................................................................................... 7
5 OVERDOSAGE................................................................................................................ 7
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................... 10
7 WARNINGS AND PRECAUTIONS.................................................................................. 10
7.1 Special Populations ............................................................................................ 18
7.1.1 Pregnant Women ......................................................................................... 18
7.1.2 Breast-feeding.............................................................................................. 19
7.1.3 Pediatrics ..................................................................................................... 19
7.1.4 Geriatrics ..................................................................................................... 20
8 ADVERSE REACTIONS .................................................................................................. 20
8.1 Adverse Reaction Overview ............................................................................... 20
8.2 Clinical Trial Adverse Reactions .......................................................................... 21
8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................. 25
8.3 Less Common Clinical Trial Adverse Reactions ................................................... 26

8.4 Abnormal laboratory findings ............................................................................ 28
8.5 Post-Market Adverse Reactions ......................................................................... 28
9 DRUG INTERACTIONS.................................................................................................. 29
9.1 Serious Drug Interactions ................................................................................... 29
9.2 Drug Interactions Overview ............................................................................... 29
9.3 Drug-Behavioural Interactions ........................................................................... 30
9.4 Drug-Drug Interactions ...................................................................................... 30
9.5 Drug-Food Interactions ...................................................................................... 33
9.6 Drug-Herb Interactions ...................................................................................... 34
9.7 Drug-Laboratory Test Interactions ..................................................................... 34
10 CLINICAL PHARMACOLOGY......................................................................................... 34
10.1 Mechanism of Action ................................................................................... 34
10.2 Pharmacodynamics ...................................................................................... 34
10.3 Pharmacokinetics ......................................................................................... 34
11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 36
12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 36
PART II: SCIENTIFIC INFORMATION ........................................................................................ 37
13 PHARMACEUTICAL INFORMATION ............................................................................. 37
14 CLINICAL TRIALS .......................................................................................................... 37
14.1 Trial Design and Study Demographics........................................................... 37
14.2 Study Results................................................................................................ 38
16 NON-CLINICAL TOXICOLOGY ....................................................................................... 38
PATIENT MEDICATION INFORMATION ................................................................................... 43

PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
PROZAC (fluoxetine) is indicated in adults for:

 Depression:
PROZAC is indicated for the symptomatic relief of Major Depressive Disorder (MDD).
 Bulimia Nervosa:
PROZAC has been shown to significantly decrease binge-eating and purging activity
when compared with placebo treatment.
 Obsessive-Compulsive Disorder (OCD):
PROZAC is indicated for the symptomatic treatment of obsessive-compulsive disorder
(OCD).
The obsessions or compulsions must be experienced as intrusive, markedly distressing,
time consuming, or interfering significantly with the person’s social or occupational
functioning.
The efficacy of PROZAC in hospitalized patients has not been adequately studied.
Long-term use of PROZAC: The effectiveness of PROZAC in long-term use in bulimia nervosa
(i.e. for more than 16 weeks) and in obsessive-compulsive disorder (i.e. for more than 13
weeks) has not been systematically evaluated in controlled trials. Therefore, the health
professional who elects to use PROZAC in these indications for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
1.1 Pediatrics
Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for pediatric use. See 7 WARNINGS AND PRECAUTIONS,
General, Potential Association with Behavioural and Emotional Changes, including Self-Harm;
see also 8.2.1. Clinical Trial Adverse Reactions – Pediatrics.
1.2 Geriatrics
Geriatrics (≥ 60 years of age): Evidence from clinical studies and experience suggests that use
in the geriatric population may be associated with differences in safety or effectiveness, and a
brief discussion can be found in the appropriate sections (4.2. Recommended Dose & Dosage
Adjustment, Special Patient Populations; 7.1.4 Geriatrics).
2 CONTRAINDICATIONS
 Hypersensitivity - PROZAC is contraindicated in patients who are hypersensitive to this

drug or to any ingredient in the formulation, including any non-medicinal ingredient, or
component of the container. For a complete listing, see 6 DOSAGE FORMS,

STRENGTHS, COMPOSITION AND PACKAGING section.
 Monoamine Oxidase Inhibitors – In patients receiving serotonin reuptake inhibitors
(SSRIs) in combination with a monoamine oxidase inhibitor (MAOI), there have been
reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and
mental status changes that include extreme agitation progressing to delirium and
coma). These reactions have also been reported in patients who have recently
discontinued SSRI treatment and then started treatment on an MAOI. Some cases
presented with features resembling neuroleptic malignant syndrome (e.g., serotonin
syndrome). PROZAC should not be used in combination with an MAOI (including the
antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue)
which are less well-known examples of MAOIs) or within 14 days of discontinuing
therapy with an MAOI.
Since fluoxetine and its major metabolite have very long elimination half-lives, at least
5 weeks should elapse after discontinuing treatment with PROZAC before starting an
MAOI. Limited reports suggest that intravenously administered dantrolene or orally
administered cyproheptadine may benefit patients experiencing such reactions. See 9.4
Drug-Drug Interactions, Monoamine-Oxidase Inhibitors section.
 Thioridazine - Thioridazine should not be administered concomitantly with PROZAC or
within a minimum of 5 weeks after PROZAC has been discontinued, nor should PROZAC
be administered within 2 weeks after thioridazine has been discontinued.
Thioridazine administration alone produces prolongation of the QTc interval, which is
associated with serious ventricular arrhythmias, such as torsades de pointes-type
arrhythmias, and sudden death. This effect appears to be dose-related.
An in vivo study suggests that drugs which inhibit P4502D6, including certain SSRI’s
such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of
thioridazine. Therefore, PROZAC should not be used in combination with thioridazine.
See 9.4 Drug-Drug Interactions, Thioridazine section.
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
General:
During maintenance therapy, the dosage should be kept at the lowest effective level.
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 PROZAC is coadministered or has been recently discontinued
(see 9.4 Drug-Drug Interactions, Tricyclic Antidepressants section).
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 PROZAC. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping
PROZAC before starting MAOI (see 2 CONTRAINDICATIONS section).
Discontinuation of Treatment:
When dosing is stopped, active drug substances will persist in the body for weeks. This should
be borne in mind when starting or stopping treatment. Dosage tapering is unnecessary in most
patients.
Despite its long-half life, symptoms associated with the discontinuation of PROZAC have been
reported in clinical trials and post-marketing. Patients should be monitored for these and
other symptoms when discontinuing treatment, regardless of the indication for which PROZAC
is being prescribed. PROZAC has been only rarely associated with such symptoms. Plasma
fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy,
which makes dose tapering unnecessary in most patients (See 7 WARNINGS AND
PRECAUTIONS and 8.1 Adverse Reaction Overview).
4.2 Recommended Dose and Dosage Adjustment
Depression:
Initial Adult Dosage: The usual initial dosage is 20 mg administered once daily in the morning.
A gradual dose increase should be considered only after a trial period of several weeks if the
expected clinical improvement does not occur. Dosage should not exceed a maximum of 60
mg per day.
Long Term: The efficacy of PROZAC in maintaining an antidepressant response for up to 38
weeks following 12 weeks of open-label acute treatment (50 weeks total) was demonstrated in
a placebo-controlled trial. The usefulness of the drug in patients receiving PROZAC for
extended periods should be reevaluated periodically (see 14.1 Trial Design and Study
Demographics section).
Bulimia Nervosa:
Adult Dosage: The recommended dosage is 60 mg per day, although studies show that lower
doses may also be efficacious. Electrolyte levels should be assessed prior to initiation of
treatment.
Obsessive-Compulsive Disorder:
A dose range of 20 mg/day to 60 mg/day is recommended for the treatment of obsessive-
compulsive disorder.
Dose Adjustment:
Since it may take up to four or five weeks to reach steady-state plasma levels of PROZAC,
sufficient time should be allowed to elapse before dosage is gradually increased. Higher
dosages are usually associated with an increased incidence of adverse reactions.

Special Patient Populations:
For any indication:
 Use in Pregnant Women:
Results of a number of epidemiological studies of pregnancy outcomes following early
maternal exposure to antidepressants have been inconsistent, but there is some evidence
of a possible small increase in the risk of cardiac malformations (e.g., ventricular and septal
defects) associated with use of fluoxetine. The mechanism is unknown. The use of PROZAC
during pregnancy should be considered only if the potential benefit justifies the potential
risk to the fetus taking into account the risks associated with untreated depression.
Post-marketing reports indicate that some neonates exposed to PROZAC, SSRIs or other
newer anti-depressants, late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding (see 7.1 Special
Populations, 7.1.1 Pregnant Women, Complications following late third trimester exposure
to SSRIs). When treating pregnant women with PROZAC during the third trimester, the
health professional should carefully consider the potential risks and benefits of treatment.
The health professional may consider tapering PROZAC in the third trimester.
 Geriatrics (≥ 60 years of age): PROZAC was evaluated in depressed elderly patients only at
a dosage of 20 mg/day. A lower or less frequent dosage may be effective and should be
considered in elderly patients with concurrent disease or on multiple medications.
 Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric
use (see 7 WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioural
and Emotional Changes, including Self-Harm).
 Renal/Hepatic Impairment or Otherwise Debilitated Patients: A lower or less frequent
dosage should be used in patients with renal and/or hepatic impairment and in those on
multiple medications.
4.4 Administration
PROZAC may be taken with or without food. The capsules should not be opened or chewed,
and they must be swallowed whole.
4.5 Missed Dose
In the event that a patient misses a dose, they should be instructed to take their dose as soon
as they can. The next dose should be taken at the next scheduled time.
5 OVERDOSAGE
Signs and Symptoms:

Cases of overdose of PROZAC alone usually have a mild course. Symptoms of overdose
included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic

arrhythmias (including nodal rhythm and ventricular arrhythmias) or ECG changes indicative of
QTc prolongation to cardiac arrest (including very rare cases of Torsade de Pointes),
pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma.
Fatalities attributed to overdose of PROZAC alone have been reported. (Please refer to Human
Experience and Animal Experience sections below).
Management of Overdosage:
There are no specific antidotes for PROZAC.
Treatment should consist of those general measures employed in the management of
overdosage with any antidepressant.
Establish and maintain an airway; ensure adequate oxygenation and ventilation.
Cardiac, electrocardiogram, and vital signs monitoring is recommended, along with general
symptomatic and supportive measures.
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 considered in treating overdose.
Due to the large volume of distribution of PROZAC, forced diuresis, dialysis, hemoperfusion,
and exchange transfusion are unlikely to be of benefit.
A specific caution involves patients who are taking or have recently taken PROZAC 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.
Fluoxetine-induced seizures which fail to remit spontaneously may respond to diazepam. (see
Product Monograph for diazepam).
In managing overdosage, consider the possibility of multiple drug involvement. The health
professional should consider contacting a poison control centre on the treatment of any
overdosage.
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 six
overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was
3 grams which was non-lethal.
Other important adverse events reported with fluoxetine overdose (single and 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 events, pyrexia stupor, and syncope.
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 hyper-irritability and convulsions in several animal species.
Among six dogs purposely overdosed with oral fluoxetine, five experienced grand mal seizures.
Seizures stopped immediately upon the bolus intravenous administration of a standard
veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at
which a seizure occurred was only twice the maximum plasma concentration seen in humans
taking 80 mg/day, chronically.
In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation
of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed.
Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the
ECG should ordinarily be monitored in cases of human overdose.
For management of a suspected drug overdose, contact your regional poison control
centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 1 – Dosage Forms, Strengths, Composition and Packaging
Route of Dosage Form /

Non-medicinal Ingredients
Administration Strength/Composition
oral capsules / 10 mg (32.3 PROZAC 10 mg and 20 mg capsules contain
µmoles) and 20 mg (64.7 benzyl alcohol, butyl paraben,
µmoles) carboxymethylcellulose sodium, edetate
calcium disodium, F D & C Blue No. 1, gelatin,
iron oxide yellow, methyl paraben, propyl
paraben, silicone, sodium propionate, sodium
lauryl sulfate, starch, and titanium dioxide.
There is no gluten, lactose, sulfite, or tartrazine

in PROZAC.
Availability of Dosage Forms:

PROZAC (fluoxetine hydrochloride) 10 mg capsules are green and green, printed with Dista
3104 and PROZAC 10 mg, packaged in amber HDPE bottles of 100.
PROZAC (fluoxetine hydrochloride) 20 mg capsules are green and yellow, printed with Dista
3105 and PROZAC 20 mg, packaged in amber HDPE bottles of 100.
7 WARNINGS AND PRECAUTIONS
General
POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING
SELF-HARM
Pediatrics - Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin
reuptake inhibitors (SSRIs) and other newer anti-depressants suggests that use of these
drugs in patients under the age of 18 may be associated with behavioural and emotional
changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
The small denominators in the clinical trial database, as well as the variability in placebo
rates, preclude reliable conclusions on the relative safety profiles among these drugs.
Adults and Pediatrics - Additional data

There are clinical trial and post-marketing reports with SSRIs and other newer anti-
depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled
with self-harm or harm to others. The agitation-type events include: akathisia, agitation,
disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the
events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal
behaviour is advised in patients of all ages. This includes monitoring for agitation- type
emotional and behavioural changes. An FDA meta-analysis of placebo-controlled clinical
trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorders
showed an increased risk of suicidal behavior with antidepressants compared to placebo.
Families and caregivers of patients being treated with PROZAC should be alerted about the
need to monitor patients for the emergence of agitation, anxiety, panic attacks, hostility,
irritability, hypomania or mania, unusual changes in behaviour, and other symptoms, as well
as the emergence of suicidality particularly within several weeks of starting treatment or
changing the dose. Such symptoms should be reported immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Discontinuation Symptoms
Patients currently taking SSRIs or newer anti-depressants should NOT be discontinued
abruptly, due to risk of discontinuation symptoms. PROZAC has only rarely been associated
with such symptoms. At the time that a medical decision is made to discontinue an SSRI or
other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt
cessation, except for fluoxetine, is recommended. Plasma fluoxetine and norfluoxetine
concentrations decrease gradually at the conclusion of therapy which makes dose tapering
unnecessary in most patients taking this drug (see 4.1 Dosing Considerations,
Discontinuation of Treatment section; 7 WARNINGS AND PRECAUTIONS,
Dependence/Tolerance; 8.1 Adverse Reaction Overview, Adverse Events Subsequent to
Discontinuation section).
Implications of the Long Elimination Half-Life of Fluoxetine

Because of the long elimination half-lives of fluoxetine and its major active metabolite
norfluoxetine, changes in dose will not be fully reflected in plasma for several weeks, affecting
both strategies for titration to final dose and withdrawal from treatment (see 4 DOSAGE AND
ADMINISTRATION; and 10 CLINICAL PHARMACOLOGY sections). Even when dosing is stopped,
active drug substance will persist in the body for weeks due to the long elimination half-lives of
fluoxetine and norfluoxetine. This is of potential consequence when drug discontinuation is
required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine
following discontinuation of PROZAC.
Use of PROZAC in Pregnant Women: Effects on Newborns

maternal exposure to antidepressants have been inconsistent, but there is some evidence of a
possible small increase in the risk of cardiac malformations (e.g., ventricular and septal
defects) associated with use of fluoxetine. The mechanism is unknown. The use of PROZAC
during pregnancy should be considered only if the potential benefit justifies the potential risk
to the fetus taking into account the risks associated with untreated depression.
Post-marketing reports indicate that some neonates exposed to PROZAC, other SSRIs (selective
serotonin reuptake inhibitors), or newer anti-depressants late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. When treating a pregnant
woman with PROZAC during the third trimester, the physician should carefully consider the
potential risks and benefits of treatment. See 4.2 Recommended Dose and Dosage
Adjustment, Special Patient Populations; and7.1 Special Populations, 7.1.1 Pregnant Women,
Complications following late third trimester exposure to SSRIs sections.
Weight Change
Significant weight loss, especially in underweight depressed patients and the elderly, may be
an undesirable result of treatment with PROZAC. PROZAC should be given with caution to
patients suffering from anorexia nervosa and only if the expected benefits (e.g., co-morbid
depression) markedly outweigh the potential weight reducing effect of the drug.
Potential for reduced efficacy of tamoxifen with concomitant SSRI use, including PROZAC
The antitumor agent tamoxifen is a pro-drug requiring metabolic activation by CYP2D6.
Inhibition of CYP2D6 can lead to reduced plasma concentrations of a primary active metabolite
(endoxifen). Chronic use of CYP2D6 inhibitors, including certain SSRIs, together with tamoxifen
can lead to persistent reduction in levels of endoxifen (see also 9.4 Drug-Drug Interactions).
Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI
antidepressants in some studies. When tamoxifen is used for the treatment of breast cancer,
prescribers should consider using an alternative antidepressant with little or no CYP2D6
inhibition.
Carcinogenesis and Mutagenesis:

For animal data, see 16 NON-CLINICAL TOXICOLOGY section.
Cardiovascular
PROZAC is associated with a risk of QTc interval prolongation (see 8.4 Abnormal laboratory
findings; 9.4 Drug-Drug Interactions, QTc-Prolonging Drugs; 10.2 Pharmacodynamics,
Electrocardiography). Rare events of torsade de pointes, ventricular fibrillation, cardiac arrest,
and sudden death have been reported with PROZAC during post-market use (see 8.5 Post-
Market Adverse Reactions). If sustained, torsade de pointes can progress to ventricular
fibrillation and sudden cardiac death.
PROZAC should be used with caution in patients with conditions such as congenital long QT
syndrome and acquired long QT syndrome (e.g., due to concomitant use of a drug that
prolongs the QT); a family history of QT prolongation; or other clinical conditions that
predispose to arrhythmias (e.g., hypokalemia or hypomagnesemia or hypocalcemia) or
increased exposure to fluoxetine (e.g., hepatic impairment). Electrocardiogram monitoring
may be warranted in patients who are suspected to be at an increased risk of experiencing
torsade de pointes, such as cardiac disease (e.g., ischemic heart disease, congestive heart
failure, history of arrhythmias), a family history of QT prolongation, recent myocardial
infarction, bradyarrhythmias, patients on concomitant medications that prolong the QTc
interval or other clinical conditions that predispose to arrhythmias (e.g., acute neurological

events, diabetes mellitus, autonomic neuropathy). Female gender and age 65 years or older
are risk factors for torsade de pointes.
When drugs that prolong the QTc interval are prescribed, health professionals should counsel
their patients concerning the nature and implications of the ECG changes, underlying diseases
and disorders that are considered to represent risk factors, demonstrated and predicted drug-
drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other
information relevant to the use of the drug.
PROZAC 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 premarketing clinical studies. The mean heart rate was reduced
by approximately 3 beats/minute.
Hypokalemia
Self-induced vomiting often leads to hypokalemia which may lower seizure threshold and/or
may lead to cardiac conduction abnormalities. Electrolyte levels of bulimic patients should be
assessed prior to initiation of treatment and at regular intervals thereafter.
Concomitant Illness:
Clinical experience with PROZAC in patients with concomitant systemic illness is limited and it
should be used cautiously in such patients, especially those with diseases or conditions that
could affect metabolism or hemodynamic responses.
Dependence/Tolerance:
Discontinuation of Treatment with PROZAC (Post-Marketing and Clinical Trials)
When discontinuing treatment, patients should be monitored for symptoms which may be
associated with discontinuation (e.g., headache, insomnia, paresthesias, nervousness, anxiety,
nausea, sweating, numbness, dizziness, jitteriness, asthenia or other symptoms which may be
of clinical significance).
PROZAC has been only rarely associated with such symptoms. Plasma fluoxetine and
norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes
dose tapering unnecessary in most patients (see 4 DOSAGE AND ADMINISTRATION, 7
WARNINGS AND PRECAUTIONS, General; and 8.1 Adverse Reaction Overview).
Dependence Liability
PROZAC has not been systematically studied, in animals or humans, for its potential for abuse,
tolerance, or physical dependence. Health professionals should carefully evaluate patients for
history of drug abuse and follow such patients closely, observing them for signs of misuse or
abuse of PROZAC.
Driving and Operating Machinery

Psychomotor Impairment: Patients should be cautioned against driving an automobile or
performing hazardous tasks until they are reasonably certain that treatment with PROZAC
does not affect them adversely.

Endocrine and Metabolism:
Diabetes
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.
Hematologic
Abnormal Bleeding
SSRIs and SNRIs, including PROZAC, may increase the risk of bleeding events by causing
abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-
inflammatory drugs (NSAIDs), warfarin and other anticoagulants may add to the risk. Case
reports and epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from
ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
SSRIs and SNRIs, including Prozac, may increase the risk of postpartum hemorrhage (7.1
Special Populations, 7.1.1 Pregnant Women, Complications following late third trimester
exposure to SSRIs).
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
PROZAC and NSAIDs, ASA, or other drugs that affect coagulation (see 9.4 Drug-Drug
Interactions, Drugs Affecting Platelet Function). Caution is advised in patients with a history of
bleeding disorder or predisposing conditions (e.g., thrombocytopenia).
Hepatic/Biliary/Pancreatic
Hepatic Impairment
Since clearances of fluoxetine and norfluoxetine may be decreased in patients with impaired
liver function including cirrhosis, a lower or less frequent dose should be used in such patients.
See 10.3 Pharmacokinetics, Special Populations and Conditions section.
Immune
Allergic Reactions (Rash and Accompanying Events): During premarketing testing, 7% of 10,782
patients developed various types of rashes and/or urticaria. Among these cases, 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 these allergic reactions
include rash, fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory
distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients
improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with
antihistamines or steroids, and all patients experiencing these events were reported to recover
completely.

In premarketing clinical trials two patients are known to have developed a serious cutaneous
systemic illness. In neither patient was there an unequivocal diagnosis, but one was
considered to have a leukocytoclastic vasculitis, and the other severe desquamation that was
considered variously to be a vasculitis or erythema multiforme. Other patients have had
systemic manifestations suggestive of serum sickness.
Since the introduction of fluoxetine, systemic events, possibly related to vasculitis, and
including lupus-like syndrome, have developed in patients with rash. Although these events
are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to
occur in association with these systemic events.
Anaphylactoid events, including bronchospasm, angioedema, laryngospasm and urticaria alone
and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis,
have been reported rarely. These events have occurred with dyspnea as the only preceding
symptom.
Whether these systemic events and rash have a common underlying cause or are due to
different etiologies or pathogenic processes is not known. Furthermore, a specific underlying
immunologic basis for these events has not been identified. Upon the appearance of rash or of
other possibly allergic phenomena for which an alternative etiology cannot be identified,
PROZAC should be discontinued. Particular caution should be exercised in patients with a
history of allergic reactions.
Musculoskeletal
Bone Fracture Risk
An increased risk of bone fractures following exposure to some antidepressants, including
SSRIs/SNRIs, was shown by epidemiological studies. The risks appear to be greater at the initial
stages of treatment, but significant increased risks were also observed at later stages of
treatment. The possibility of fracture should be considered in the care of patients treated with
PROZAC. Elderly patients and patients with important risk factors for bone fractures should be
advised of possible adverse events which increase the risk of falls, such as dizziness and
orthostatic hypotension, especially at the early stages of treatment but also soon after
withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and
low bone mineral density in older men and women. Until further information becomes
available, a possible effect on bone mineral density with long term treatment with
SSRIs/SNRIs, including PROZAC, cannot be excluded, and may be a potential concern for
patients with osteoporosis or major risk factors for bone fractures.
Neurologic
Seizures
PROZAC should be used with caution in patients with a history of convulsive disorders. The
incidence of seizures associated with fluoxetine during clinical trials did not appear to differ
from that reported with other marketed antidepressants; however, patients with a history of
convulsive disorders were excluded from these trials.

Concurrent administration with electroshock therapy should be avoided because of the
absence of experience in this area. There have been rare reports of prolonged seizures in
patients on fluoxetine receiving ECT treatment.
Serotonin Syndrome /Neuroleptic Malignant Syndrome
On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have
occurred in association with treatment with SSRIs, including PROZAC, particularly when given
in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may
result in potentially life-threatening conditions, treatment with PROZAC should be
discontinued if such events (characterized by clusters of symptoms such as hyperthermia,
rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental
status changes including confusion, irritability, extreme agitation progressing to delirium and
coma) occur and supportive symptomatic treatment should be initiated. Due to the risk of
serotonergic syndrome or neuroleptic malignant syndrome, PROZAC should not be used in
combination with MAO inhibitors (including the antibiotic linezolid and the thiazine dye
methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs) or
serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in
combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium,
tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see 2
CONTRAINDICATIONS and 9.4 Drug-Drug Interactions, Serotonergic Drugs).
Ophthalmologic
Angle-Closure Glaucoma
As with other antidepressants, PROZAC can cause mydriasis, which may trigger an angle-
closure attack in a patient with anatomically narrow ocular angles. Healthcare providers
should inform patients to seek immediate medical assistance if they experience eye pain,
changes in vision or swelling or redness in or around the eye.
Psychiatric
Suicide risk
The possibility of a suicide attempt is inherent in depression and other psychiatric disorders
and may persist until significant remission occurs. As with other drugs with similar
pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal
behaviors have been reported during fluoxetine therapy or early after treatment
discontinuation.
Although a causal role for fluoxetine in inducing such events has not been established, an FDA
analysis from pooled studies of antidepressants in psychiatric disorders found an increased risk
for suicidal ideation and/or suicidal behaviors in pediatric and young adult (< 25 years of age)
patients compared to placebo.
Close supervision of high-risk patients should accompany drug therapy and consideration
should be given to the possible need for hospitalization. Health professionals should
encourage patients of all ages to report any new or worsened distressing thoughts or feelings
occurring at any time. In order to minimize the opportunity for overdosage, prescriptions for

fluoxetine should be written for the smallest quantity of drug consistent with good patient
management.
Because of the well established comorbidity between depression and other psychiatric
disorders, the same precautions observed when treating patients with depression should be
observed when treating patients with other psychiatric disorders (see 7 WARNINGS AND
PRECAUTIONS, General, Potential Association with Behavioral and Emotional Changes,
Including Self-Harm).
Activation of Mania/Hypomania
During premarketing clinical trials in a patient population comprised primarily of unipolar
depressed patients, hypomania or mania occurred in approximately 1% of fluoxetine treated
patients. The incidence in a general patient population which might also include bipolar
depressives is unknown. The likelihood of hypomanic or manic episodes may be increased at
the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of
the drug.
A major depressive episode may be the initial presentation of bipolar disorder. Patients with
bipolar disorder may be at an increased risk of experiencing manic episodes when treated with
antidepressants alone. Therefore, the decision to initiate symptomatic treatment of
depression should only be made after patients have been adequately assessed to determine if
they are at risk for bipolar disorder.
Electroconvulsive Therapy (ECT)
There are no clinical studies to support the safety and efficacy of combined use of ECT and
fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine
receiving ECT treatment.
Renal
Severe Renal Impairment
Since fluoxetine is extensively metabolized, excretion of unchanged drug in urine is a minor
route of elimination. However, until an adequate number of patients with severe renal
impairment have been evaluated in the course of chronic treatment, fluoxetine should be used
with caution in such patients.
Hyponatremia
Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been
reported. The hyponatremia appeared to be reversible when PROZAC was discontinued.
Although these cases were complex with varying possible etiologies, some were possibly due
to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of
these occurrences have been in older patients and in patients taking diuretics or who were
otherwise volume depleted.
In two 6-week controlled studies in patients ≥ 60 years of age, 10 of 323 fluoxetine patients
and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range;
this difference was not statistically significant. The lowest observed concentration of sodium in

a fluoxetine treated patient was 129 mmol/L. The observed decreases were not clinically
significant.
Reproductive Health: Female and Male Potential

 Fertility
Male Fertility
Animal data have shown that PROZAC at levels in excess of the maximum tolerable dose
may affect sperm quality (See 16 NON-CLINICAL TOXICOLOGY, General Toxicology, and
Reproductive and Developmental Toxicology). In human case reports, some reversible
changes in sperm quality have been reported with some SSRIs, including PROZAC. An
impact on human fertility has not been observed.
7.1 Special Populations
7.1.1 Pregnant Women
Pregnant Women and Newborns

There are no adequate and well-controlled clinical studies on the use of PROZAC in pregnant
women. PROZAC should not be administered to pregnant women or those intending to
become pregnant unless in the opinion of the treating health professional, the expected
benefits to the patient markedly outweigh the possible hazards to the fetus or the child.
See also: 4.2 Recommended Dose and Dosage Adjustment, Special Patient Populations; and, 7
WARNINGS AND PRECAUTIONS, General, Use of PROZAC in Pregnant Women: Effects on
Newborns sections.
Possible Risk of Cardiovascular Malformations following first trimester exposure to SSRIs

maternal exposure to antidepressants have been inconsistent, with some finding no increased
risk of malformations with fluoxetine exposure, while others have found a small increased risk
for cardiovascular malformations (e.g., ventricular and septal defects) in infants with first
trimester exposure to fluoxetine compared to those not exposed. The mechanism is unknown.
Overall, the data suggest that the potential risk of having an infant with a cardiovascular
malformation following maternal exposure to PROZAC is less than 2/100 compared with an
expected rate for such defects of approximately 1/100 in the general population. The use of
PROZAC during pregnancy should be considered only if the potential benefit justifies the
potential risk to the fetus taking into account the risks associated with untreated depression.
Complications following late third trimester exposure to SSRIs

Post-marketing reports indicate that some neonates exposed to PROZAC, other SSRIs (selective
serotonin reuptake inhibitors), or newer anti-depressants 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 SSRIs and other newer anti-depressants or, possibly, a drug discontinuation syndrome. It
should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
(see 2 CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).
Observational data suggests an increased risk (less than 2-fold) of postpartum hemorrhage
following SSRI/SNRI exposure within a month of delivery, including fluoxetine (see 7
WARNINGS AND PRECAUTIONS, Hematologic, Abnormal Bleeding).
When treating a pregnant woman with PROZAC during the third trimester, the health
professional should carefully consider the potential risks and benefits of treatment (see 4.2
Recommended Dose and Dosage Adjustment, Special Patient Populations section).
Risk of PPHN and exposure to SSRIs (including fluoxetine)

Exposure during late pregnancy to SSRIs, including PROZAC, may have an increased risk for
persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live
births in the general population and is associated with substantial neonatal morbidity and
mortality. In a retrospective case-control study of 377 women whose infants were born with
PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was
approximately 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. A study
of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3)
associated with patient-reported maternal use of SSRIs in “early pregnancy” and a PPHN risk
ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of
SSRIs in “early pregnancy” and an antenatal SSRI prescription in “later pregnancy”.
7.1.2 Breast-feeding
PROZAC and its metabolites are excreted in breast milk, and have been observed to reach high
levels in the plasma of nursing infants. Women who are taking PROZAC should not breast feed
unless, in the opinion of the treating health professional, breast feeding is necessary, in which
case the infant should be closely monitored.
In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL.
The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant
were reported. In another case, a 6-week infant, nursed by a mother on PROZAC, developed
crying, decreased sleep, vomiting and watery stools. The breast milk showed concentrations of
69 ng/mL for fluoxetine and 90 ng/mL for norfluoxetine. In the infant’s plasma, the
concentrations of fluoxetine and norfluoxetine on the second day of feeding were 340 and 208
ng/mL, respectively.
7.1.3 Pediatrics
Pediatrics (< 18 years of age):No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for pediatric use. See 7 WARNINGS AND PRECAUTIONS,
General, Potential Association with Behavioural and Emotional Changes, including Self-Harm.

See also 8.2.1 Clinical Trial Adverse Reactions – Pediatrics, Potential for Effects on Growth in
Pediatric Patients.
7.1.4 Geriatrics
Geriatrics (≥ 60 years of age): Evaluation of patients over the age of 60 who received PROZAC
20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in
younger patients. These data are however insufficient to rule out possible age-related
differences during chronic use, particularly in elderly patients who have concomitant systemic
illnesses or who are receiving concomitant drugs. See 1 INDICATIONS, and 4.2 Recommended
Dose and Dosage Adjustment, Special Patient Populations sections.
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
Commonly Observed Adverse Events

In clinical trials, the most commonly observed adverse events associated with the use of
PROZAC and not seen at an equivalent incidence among placebo treated patients were: central
nervous system complaints, including headache, nervousness, insomnia, drowsiness, fatigue or
asthenia, anxiety, tremor, and dizziness or lightheadedness; gastrointestinal complaints,
including nausea, diarrhea, dry mouth and anorexia; and excessive sweating.
Adverse Events Leading to Discontinuation of Treatment
Fifteen percent of approximately 4,000 patients who received PROZAC in North American
clinical trials discontinued treatment due to an adverse event. The more common events
causing discontinuation from depression trials in adults and elderly, included: psychiatric,
primarily nervousness, anxiety, and insomnia; digestive, primarily nausea; nervous system,
primarily dizziness, asthenia, and headaches; skin, primarily rash and pruritus.
In obsessive compulsive disorder studies, 12.1% of fluoxetine treated patients discontinued
treatment early because of adverse events. Anxiety and rash, at incidences of less than 2%,
were the most frequently reported events. In bulimia nervosa studies, 10.2% of fluoxetine
treated patients discontinued treatment early because of adverse events. Insomnia, anxiety
and rash, at incidences of less than 2%, were the most frequently reported events.
Adverse Events Subsequent to Discontinuation
Symptoms associated with discontinuation of PROZAC have been reported in clinical trials and
post-marketing (e.g., headache, insomnia, paresthesias, nervousness, anxiety, nausea,
sweating, numbness, dizziness, jitteriness, asthenia, or other symptoms which may be of
clinical significance). The majority of these are mild and self–limiting. PROZAC has been only
rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations
decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in
most patients. See 4.1 Dosing Considerations, Discontinuation of Treatment; and 7 WARNINGS
AND PRECAUTIONS, General.

Serious Adverse Reactions
Suicidal thoughts and acts are far more common among depressed patients than in the
general population. It is estimated that suicide is 22 to 36 times more prevalent in depressed
persons than in the general population. A comprehensive meta-analysis of pooled data from
17 double blind clinical trials in patients with major depressive disorder compared fluoxetine
(n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. The pooled
incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for
placebo, and 3.6% for tricyclic antidepressants.
In countries where the drug has already been marketed, the following potentially serious
adverse reactions have been reported; interactions with MAO inhibitors and possibly other
drugs, allergic reactions, cardiovascular reactions, syndrome of inappropriate ADH secretion,
and grand mal seizure. Death and life-threatening events have been associated with some of
these reactions, although causal relationship to PROZAC has not necessarily been established.
Post-marketing experience also confirms the profile of adverse reactions commonly reported
during clinical trials with PROZAC including allergic skin reactions.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse drug reaction rates
observed in the clinical trials; therefore, may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials of another drug. Adverse drug
reaction information from clinical trials may be useful in identifying and approximating rates of
adverse drug reactions in real-world use.
Multiple doses of PROZAC had been administered to 10,782 patients with various diagnoses in
US clinical trials as of May 8, 1995. Adverse events 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 events without
first grouping similar types of events into a limited (i.e., reduced) number of standardized
event categories.
Adults:
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to
classify reported adverse events. The stated frequencies represent the proportion of
individuals who experienced, at least once, a treatment-emergent adverse event of the type
listed. An event 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 events 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 health professional with some basis for estimating the

relative contribution of drug and nondrug factors to the side effect incidence rate in the
population studied.
Table 2: Treatment-Emergent Adverse Events Incidence in Fluoxetine versus Placebo Trials
Listed by Indication
Percentage of Patients Reporting Event
DEPRESSION* DEPRESSION
(Adults) (Elderly) OCD* BULIMIA*
Body System/ Fluoxetine Placebo Fluoxetine Placebo Fluoxetine Placebo Fluoxetine Placebo
Adverse Event (N=1728) (N=975) (N=335) (N=336) (N=266) (N=89) (N=450) (N=267)
Nervous System
Headache -- -- 28 24 -- -- -- --
Nervousness 14 9 12 7 14 15 11 5
Insomnia 16 9 18 12 28 22 33 13
Somnolence 13 6 9 6 17 7 13 5
Anxiety 12 7 13 8 14 7 15 9
Tremor 10 3 8 4 9 1 13 1
Dizziness -- -- 11 10 -- -- -- --
Libido, decreased 3 0 -- -- 11 2 5 1
Abnormal dreams 1 1 -- -- 5 2 5 3
Digestive System
Nausea 21 9 17 7 26 13 29 11
Diarrhea -- -- 14 9 -- -- -- --
Dry mouth 10 7 7 5 12 3 9 6
Anorexia 11 2 11 2 17 10 8 4
Dyspepsia 7 5 11 5 10 4 10 6
Constipation -- -- 7 6 -- -- -- --
Flatulence -- -- 7 2 -- -- -- --
Skin and Appendages
Sweating 8 3 7 3 7 0 8 3
Rash 4 3 -- -- 6 3 4 4
Body as a Whole
Asthenia 9 5 13 10 15 11 21 9
Flu syndrome 3 4 -- -- 10 7 8 3
Back Pain -- -- 7 9 -- -- -- --
Abdominal Pain -- -- 6 6 -- -- -- --
Myalgia -- -- 3 5 -- -- -- --
Respiratory System
Rhinitis -- -- 9 14 -- -- -- --
Pharyngitis 3 3 -- -- 11 9 10 5
Sinusitis 1 4 3 7 5 2 6 4
Yawn -- -- -- -- 7 -- 11 --
Cardiovascular System
Vasodilatation 3 2 -- -- 5 0 2 1
Urogenital System
Abnormal Ejaculation† -- -- -- -- 7 -- 7 --
Impotence† 2 -- -- -- -- -- 7 --

† Denominator used was for males only (N= 690 PROZAC depression; N=410 placebo depression; N=116 PROZAC OCD;
N=43 placebo OCD; N=14 PROZAC bulimia; N=1 placebo bulimia).
-- Incidence less than 1%
* The most common treatment-emergent adverse events associated with the use of PROZAC (incidence of at least 5%
for PROZAC and at least twice that for placebo within at least one of the indications) for the treatment of depression,
OCD, and bulimia in US controlled clinical trials.
Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more patients

treated with PROZAC and with incidence greater than placebo who participated in US
controlled clinical trials comparing PROZAC with placebo in the treatment of depression, OCD,
or bulimia. Table 3 provides combined data for the pool of studies that are provided separately
by indication in Table 2.
Table 3: Combined Treatment-Emergent Adverse Events Incidence for Patients Treated with
PROZAC versus Placebo
Percentage of patients reporting event
Depression, OCD, and bulimia combined
Body System/Adverse Event * PROZAC (N=2444) Placebo (N=1331)
Body as a Whole
Headache 21 20
Asthenia 12 6
Flu syndrome 5 4
Fever 2 1
Vasodilatation 3 1
Palpitation 2 1
Digestive System
Nausea 23 10
Diarrhea 12 8
Anorexia 11 3
Dry mouth 10 7
Dyspepsia 8 5
Flatulence 3 2
Vomiting 3 2
Metabolic and Nutritional Disorders
Weight loss 2 1
Nervous System
Insomnia 20 11
Anxiety 13 8
Nervousness 13 9
Somnolence 13 6
Dizziness 10 7
Tremor 10 3
Libido decreased 4 --
Respiratory System
Pharyngitis 5 4
Yawn 3 --
Skin and Appendages

Sweating 8 3
Rash 4 3
Pruritus 3 2
Special Senses
Abnormal vision 3 1
* Included are events reported by at least 2% of patients taking PROZAC, except the following events,
which had an incidence on placebo
> PROZAC (depression, OCD, and bulimia combined): abdominal pain, abnormal dreams, accidental injury,
back pain, chest pain, constipation, cough increased, depression (includes suicidal thoughts),
dysmenorrhea, gastrointestinal disorder, infection, myalgia, pain, paresthesia, rhinitis, sinusitus, thinking
abnormal.
-- Incidence less than 1%.
Table 4 lists the adverse events associated with discontinuation of PROZAC treatment
(incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting
only a primary event associated with discontinuation) in depression, OCD, and bulimia. For
symptoms associated with discontinuation of PROZAC in clinical trials and post-marketing, see
8.5 Post-Market Adverse Reactions section.
Table 4: Adverse Events Associated with Discontinuation of PROZAC Treatment

Depression, OCD, and
Bulimia Combined Depression OCD Bulimia
(N=1108) (N=392) (N=266) (N=450)
-- -- Anxiety (2%) --
Insomnia (1%) -- -- Insomnia (2%)
-- Nervousness (1%) -- --
-- -- Rash (1%) --
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 health professionals 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 depression, OCD, and bulimia
placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by
at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been
spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including
anorgasmia.
There are no adequate and well-controlled studies examining sexual dysfunction with
fluoxetine treatment. Symptoms of sexual dysfunction occasionally persisting after

discontinuation of fluoxetine treatment have been observed in spontaneous reports. 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, health professionals should routinely inquire
about such possible side effects.
Other Frequent Treatment Emergent Adverse Events

The following is a list of additional treatment emergent adverse events reported frequently
(i.e., occurring on 1 or more occasions in at least 1/100 patients) at any time by individuals
taking fluoxetine in US clinical trials (10, 782 patients):
Body as a Whole: chills
Cardiovascular system: hemorrhage, hypertension
Digestive system: increased appetite, nausea and vomiting
Metabolic and Nutritional: weight gain
Nervous System: abnormal movement/tremor1, agitation, amnesia, confusion,
emotional lability, fatigue2, headache, sleep abnormalities3
Special Senses: ear pain, taste perversion, tinnitus
Urogenital System: gynaecological bleeding*, sexual dysfunction*,4 urinary frequency
8.2.1 Clinical Trial Adverse Reactions – Pediatrics
Pediatrics (< 18 years of age):

Frequent: epistaxis
Potential for Effects on Growth in Pediatric Patients:

PROZAC is not indicated for use in patients below the age of 18 years (see WARNINGS AND
PRECAUTIONS, General, Potential Association with Behavioural and Emotional Changes,
including Self-Harm).
Decreased weight gain and a lesser gain in height have 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 (n = 88) were recorded as gaining an average of
1.1 cm less in height than subjects treated with placebo (n = 75). However, the study was not
designed for a rigorous assessment of growth (e.g., heights were recorded to the nearest
rounded inch), and thus a definite interpretation of this finding was compromised. This is
exemplified by the reported outcome of a loss in height for 17 of the patients.
Notwithstanding these limitations, an attenuation of height gain with acute fluoxetine
treatment cannot be excluded. (See also 16 NON-CLINICAL TOXICOLOGY, Juvenile Toxicity).
Fluoxetine treatment was also associated with a decrease in serum alkaline phosphatase levels
in this study. 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.

8.3 Less Common Clinical Trial Adverse Reactions
Treatment-Emergent Adverse Events

Following is a list of all treatment-emergent adverse events reported at anytime by individuals
taking fluoxetine in US clinical trials (10,782 patients) except: (1) those listed in the body or
footnotes of Tables 2 or 3 above or elsewhere in labelling; (2) those for which the COSTART
terms were uninformative or misleading; (3) those events for which a causal relationship to
PROZAC use was considered remote; and (4) events occurring in only 1 patient treated with
PROZAC and which did not have a substantial probability of being acutely life-threatening.
Events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: infrequent adverse events are those
occurring in less than 1/100 but at least 1/1,000 patients; rare events are those occurring in
less than 1/1,000 patients.
Body as a Whole
Infrequent: chills and fever, face edema, feeling abnormal, intentional overdose,
malaise, pelvic pain, suicide attempt.
Rare: abdominal syndrome acute, hypothermia, intentional injury, neuroleptic malignant
syndrome‡, photosensitivity reaction.
*characterized by the clustering of clinical features of changes in mental state and
neuromuscular activity, in combination with autonomic nervous system dysfunction.
Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine,
myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache.
Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia,
cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral
vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular
arrhythmia, ventricular extrasystoles, ventricular fibrillation.
1
COSTART group term abnormal movement/tremor includes the independent terms: frequent: tremor; infrequent: ataxia,
buccoglossal, myoclonus; rare: twitching.
2
COSTART group term fatigue includes the independent terms: frequent: asthenia, somnolence.
3
COSTART group term sleep abnormalities includes the independent terms: frequent: insomnia; rare: abnormal dreams.
* Adjusted for gender
4
COSTART group term sexual dysfunction includes the independent terms: frequent: impotence, libido decreased;
infrequent: anorgasmia, delayed or absent ejaculation.
‡
Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome.
† Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.
Digestive System
Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis,
gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased
salivation, liver function tests abnormal, melena, mouth ulceration,
nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst.

Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal
ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of
colon, hepatitis, intestinal obstruction, liver fatty deposit, oesophageal pain, pancreatitis,
peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage,
tongue edema.
Endocrine System
Infrequent: hypothyroidism
Rare: diabetic acidosis, diabetes mellitus.
Hemic and Lymphatic System
Infrequent: anemia, ecchymosis.
Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis,
petechia, purpura, thrombocythemia, thrombocytopenia.
Metabolic and Nutritional
Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia,
hypokalemia, peripheral edema.
Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine
phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency
anemia, SGPT increased.
Musculoskeletal System
Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis.
Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis,
osteoporosis, rheumatoid arthritis.
Nervous System
Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, balance disorder,
bruxism, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations,
hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased,
neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder†, psychosis,
vertigo.
Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia,
coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop,
hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor.
† Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.
Respiratory System
Infrequent: asthma, epistaxis, hiccup, hyperventilation.
Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation,
hypoxia, larynx edema, lung edema, pneumothorax, stridor.

Skin and Appendages
Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin
discoloration, skin ulcer, vesiculobullous rash.
Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash,
pustular rash, seborrhea.
Special Senses
Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia.
Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma,
hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.
Urogenital System
Infrequent: abortion*, albuminuria, amenorrhea*, breast enlargement, breast pain,
cystitis, dysuria, female lactation*, fibrocystic breast*, hematuria, leukorrhea*,
menorrhagia*, metrorrhagia*, nocturia, polyuria, urinary incontinence, urinary
retention, urinary urgency.
Rare: breast engorgement, glycosuria, hypomenorrhea*, kidney pain, oliguria, priapism*,
uterine fibroids enlarged*.
* Adjusted for gender.
8.4 Abnormal laboratory findings
ECG Findings:
In a placebo-controlled clinical trial in major depressive disorder, fluoxetine titrated to doses in
the range of 40-80 mg/day was associated with a statistically significant placebo-adjusted
mean change from baseline in the Fridericia-corrected QT interval (QTcF=QT/RR0.33) of 8.6 ms
(90% CI 4.5, 12.6). See 7 WARNINGS AND PRECAUTIONS, Cardiovascular; 9.4 Drug-Drug
Interactions, QTc-Prolonging Drugs; 10.2 Pharmacodynamics, Electrocardiography
8.5 Post-Market Adverse Reactions
Voluntary reports of adverse events temporally associated with PROZAC that have been
received since market introduction and that may have no causal relationship with the drug
include the following: aplastic anemia, atrial fibrillation, bone fractures, cardiac arrest,
cataract, cerebral vascular accident, cholestatic jaundice, confusion, 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, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative
dermatitis, gastrointestinal bleeding5, galactorrhea, gynecomastia, heart arrest, hepatic
failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney
failure, memory impairment, misuse/abuse, movement disorders developing in patients with
risk factors including drugs associated with such events and worsening of preexisting
movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis,
pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation,
serotonin syndrome (a range of signs and symptoms that can rarely, in most severe cases,
resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected
death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after
drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias and
ventricular fibrillation) and violent behaviours.
5
Includes: esophageal varices hemorrhage, gingival and mouth bleeding, hematemesis, hematochezia, hematomas
[intraabdominal, peritoneal], hemorrhage [anal, esophageal, gastric, gastrointestinal (upper and lower), haemorrhoidal,
peritoneal, rectal], hemorrhagic diarrhoea and enterocolitis, hemorrhagic diverticulitis, hemorrhagic gastritis, melaena, and
ulcer hemorrhage [esophageal, gastric,duodenal]
9 DRUG INTERACTIONS
9.1 Serious Drug Interactions
Serious Drug Interactions

 Monoamine Oxidase Inhibitors: See 2 CONTRAINDICATIONS and 9.4 Drug-Drug
Interactions
 Thioridazine: See 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions
9.2 Drug Interactions Overview
PROZAC, like some other agents that are metabolized by the P4502D6 system, inhibits the
activity of this isoenzyme. Therefore, co-therapy with medications that are predominantly
metabolized by the P4502D6 system and that have a relatively narrow therapeutic index (e.g.,
flecainide, encainide, vinblastine, carbamazepine and tricyclic antidepressants) 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. If fluoxetine is added to the treatment regimen of a
patient already receiving a drug metabolized by P4502D6, the need for decreased dose of the
original medication should be considered. The aforementioned drugs with a narrow
therapeutic index represent the greatest concern.
Other drugs that have demonstrated increased plasma values or magnified effects when co-
administered with fluoxetine include: phenytoin, antipsychotics, benzodiazapines, thioridazine
(see 2 CONTRAINDICATIONS), St. John’s Wort and warfarin.
As fluoxetine is highly bound to plasma proteins, co-administration with another drug which is
also highly bound (e.g., warfarin, digitoxin) may result in adverse effects due to an increase in
plasma levels of either unbound drug.
There are little data available on the concomitant use of fluoxetine and alcohol.

9.3 Drug-Behavioural Interactions
Alcohol: The concomitant use of fluoxetine and alcohol on cognitive and psychomotor effects
in depressed, panic disorder or OCD patients is not known and is not recommended.
Interaction with lifestyle interactions have not been established.
9.4 Drug-Drug Interactions
QTc-Prolonging Drugs: Pharmacokinetic and pharmacodynamic studies of fluoxetine combined

with other medicinal products that prolong the QT interval have not been performed. An
additive effect of fluoxetine and these medicinal products cannot be excluded. Therefore, co-
administration of fluoxetine with medicinal products that have a clear QT interval prolonging
effect is discouraged. Drugs that have been associated with QTc interval prolongation and/or
torsade de pointes include, but are not limited to, the examples in the following list.
Chemical/pharmacological classes are listed if some, although not necessarily all, class
members have been implicated in QTc prolongation and/or torsade de pointes:
 Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide)
 Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone)
 Class 1C antiarrhythmics (e.g., flecainide, propafenone)
 antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone)
 antidepressants (e.g., citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g.,
amitriptyline, imipramine, maprotiline)
 opioids (e.g., methadone)
 macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin,
tacrolimus)
 quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin)
 antimalarials (e.g., quinine, chloroquine)
 azole antifungals (e.g., ketoconazole, fluconazole, voriconazole)
 domperidone
 5-HT3 receptor antagonists (e.g., dolasetron, ondansetron)
 tyrosine kinase inhibitors (e.g., vandetanib, sunitinib, nilotinib, lapatinib)
 histone deacetylase inhibitors (e.g., vorinostat)
 beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).
Drugs that Affect Electrolytes: The concomitant use of PROZAC with drugs that can disrupt
electrolyte levels is discouraged. Drugs that decrease electrolyte levels include, but are not
limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas;
amphotericin B; high dose corticosteroids.
The above lists of potentially interacting drugs are not comprehensive. (See also 7 WARNINGS
AND PRECAUTIONS, Cardiovascular; 8.4 Abnormal laboratory findings & 8.5 Post-Market
Adverse Reactions; 10.2 Pharmacodynamics, Electrocardiography).
Monoamine Oxidase Inhibitors: Combined use of PROZAC and MAO inhibitors (including the
antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are
less well-known examples of MAOIs) is contraindicated due to the potential for serious
reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome
(See 2 CONTRAINDICATIONS; 7 WARNINGS AND PRECAUTIONS, Serotonin
Syndrome/Neuroleptic Malignant Syndrome).
Thioridazine: Potential Interactions with Thioridazine (see also 2 CONTRAINDICATIONS): In a
study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of
debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a
4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid
hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of
cytochrome P4502D6 isozyme activity. Thus, this study suggests that drugs which inhibit
P4502D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of
thioridazine.
Thioridazine administration produces a dose-related prolongation of the QTc interval which is
associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias,
and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of
thioridazine metabolism. Due to the risk of serious ventricular arrhythmias and sudden death
potentially associated with elevated plasma levels of thioridazine, thioridazine should not be
concomitantly administered, nor within a minimum of 5 weeks after fluoxetine has been
discontinued, nor should PROZAC be administered within 2 weeks after thioridazine has been
discontinued (see 2 CONTRAINDICATIONS).
Drugs Affecting Platelet Function (e.g., NSAIDS, ASA and other anticoagulants): 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, ASA or other anticoagulants may
potentiate the risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or
SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be
carefully monitored when fluoxetine is initiated or discontinued [see 7 WARNINGS AND
PRECAUTIONS, Hematologic, Abnormal Bleeding].
Drugs Tightly Bound to Plasma Protein: Because fluoxetine is highly bound to plasma protein,
the administration of fluoxetine to a patient taking another drug which is tightly bound to
protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially
resulting in an adverse effect. Conversely, adverse effects may result from displacement of
protein bound fluoxetine by other tightly bound drugs.
Drugs Metabolized by P4502D6 Isoenzyme: Approximately 3 to 10% of the normal population
has a genetic defect that leads to reduced levels of activity of the cytochrome P450 isoenzyme
P4502D6. Such individuals have been referred to as "poor metabolizers" of drugs such as
debrisoquine, dextrometorphan, sparteine, tricyclic antidepressants (e.g., nortryptiline,
amitriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g., perphenazine
and thioridazine) and Type 1C antiarrhythmics (e.g., propafenone and flecainide).

Conversely, approximately 90 to 97% of the normal population do not have this genetic defect,
and are known as "extensive metabolizers". PROZAC, like other agents that are metabolized by
the P4502D6 system, inhibits the activity of this iso enzyme, and thus may make normal
"extensive" metabolizers resemble "poor metabolizers". Therapy with medications that are
predominantly metabolized by the P4502D6 system and that have a relatively narrow
therapeutic index (e.g., flecainide, encainida, vinblastine, carbamazepine and tricyclic
antidepressants) 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.
If fluoxetine is added to the treatment regimen of a patient already receiving a drug
metabolized by P4502D6 the need for decreased dose of the original medication should be
considered. The aforementioned drugs with a narrow therapeutic index represent the greatest
concern.
Tamoxifen: Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a
65-75% reduction in plasma levels of one of the more active forms of the tamoxifen, i.e.,
endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been
reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced
effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors
(including fluoxetine) should whenever possible be avoided (see 7 WARNINGS AND
PRECAUTIONS).
Impact of CYP2D6 Inhibition on Fluoxetine Metabolism: Both the pharmacokinetic properties
and relative proportion of metabolites of fluoxetine may be affected by a patient’s CYP2D6
pharmacogenetic phenotype, or by a number of different drugs known to inhibit the CYP2D6
enzyme.
Drugs Metabolized by Cytochrome P4503A4: In an in vivo interaction study involving co -
administration of fluoxetine with single doses of terfenadine (a cytochrome P4503A4
substrate), no increase in plasma terfenadine concentrations occurred with concomitant
fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of
P4503A4 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
cytochrome P4503A4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants: In two studies, previously stable plasma levels of imipramine and
desipramine have increased greater than 2 to 10-fold when fluoxetine has been administered
in combination. This influence may persist for three weeks or longer after fluoxetine is
discontinued. Thus, the dose of tricyclic antidepressant (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 7 WARNINGS AND PRECAUTIONS; and
10.3 Pharmacokinetics, Accumulation and Slow Elimination sections.
Lithium: There have been reports of both increased and decreased lithium levels when lithium
was used concomitantly with fluoxetine. Cases of lithium toxicity have been reported. Lithium
levels should be monitored when these drugs are administered concomitantly.

Tryptophan: Five patients receiving PROZAC in combination with tryptophan experienced
adverse reactions, including agitation, restlessness and gastrointestinal distress.
Benzodiazepines: The half-life of concurrently administered diazepam may be prolonged in
some patients.
Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma
concentrations and in further psychomotor performance decrement due to increased
alprazolam levels. Consideration should be given to monitoring of clinical status. Experience
with the use of PROZAC in combination with other CNS-active drugs is limited and caution is
advised if such concomitant medication is required.
Antipsychotics: Elevation of blood levels of haloperidol and clozapine and in some cases,
clinical manifestations of toxicity have been observed with coadministration of fluoxetine.
Consideration should be given to monitoring of clinical status.
Serotonergic Drugs: Based on the mechanism of action of fluoxetine and the potential for
serotonin syndrome, caution is advised when PROZAC is coadministered with other drugs or
agents that may affect the serotonergic neurotransmitter systems, such as tryptophan,
triptans, serotonin reuptake inhibitors, linezolid (an antibiotic which is a reversible non-
selective MAOI), lithium, tramadol, fentanyl and its analogues, dextromethorphan, tapentadol,
meperidine, methadone, pentazocine or St. John's Wort (see 7 WARNINGS AND PRECAUTIONS,
Serotonin Syndrome/Neuroleptic Malignant Syndrome).
Triptans (5HT1 agonists): There have been rare postmarketing reports describing patients with
weakness, hyperreflexia, and incoordination following the use of a selective serotonin
reuptake inhibitor (SSRI) and the 5HT1 agonist, sumatriptan. If concomitant treatment with
triptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) is
clinically warranted, appropriate observation of the patient is advised. The possibility of such
interactions should also be considered if other 5HT1 agonists are to be used in combination
with SSRIs (see 7 WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant
Syndrome).
Phenytoin: In patients on stable, maintenance doses of phenytoin, plasma phenytoin
concentrations increased substantially and symptoms of phe nytoin toxicity appeared
(nystagmus, diplopia, ataxia and CNS depression) following initiation of concomitant fluoxetine
treatment.
Carbamazepine: Patients on stable doses of phenytoin and carbamazepine have developed
elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following
initiation of concomitant fluoxetine treatment. Consideration should be given to monitoring of
clinical status when fluoxetine treatment is initiated in these patients.
9.5 Drug-Food Interactions
Absorption of fluoxetine is not affected by food.

9.6 Drug-Herb Interactions
St. John’s Wort: In common with other SSRI’s, pharmacodynamic interactions between
fluoxetine and the herbal remedy St. John’s Wort may occur and may result in an increase in
undesirable effects.
9.7 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
The mechanism of PROZAC is unknown. The antidepressant, antiobsessional, and antibulimic

actions of PROZAC are presumed to be linked to its ability to selectively inhibit the neuronal
reuptake of serotonin. At clinically relevant doses fluoxetine blocks the uptake of serotonin
into human platelets.
10.2 Pharmacodynamics
Antagonism of muscarinic, histaminergic and α1- adrenergic receptors has been hypothesized
to be associated with various anticholinergic, sedative and cardiovascular effects of classical
tricyclic antidepressant drugs. In vitro receptor binding studies have demonstrated that
fluoxetine binds to these and other membrane receptors [opiate, serotonergic (5-HT1, 5-HT2),
adrenergic (α1,α2,β) and dopaminergic] much less potently than do the tricyclic drugs.
Electrocardiography:
A double-blind, placebo-controlled, randomised, multiple dose study was performed in two
cohorts of healthy adult subjects (CYP2D6 intermediate and extensive metabolizers). In the
first cohort, subjects received once-daily oral dosing for 28 days with fluoxetine 20 mg (N = 12)
or placebo (N = 4), whilst in the second cohort, subjects received once-daily oral dosing for 28
days with fluoxetine 40 mg (N = 12) or placebo (N = 4). Serial ECG assessments were
performed at baseline and on days 1 and 28 of treatment. For the 40 mg fluoxetine treatment
(N = 12), the maximal mean difference from placebo in change from time- averaged baseline in
QTcF (QT/RR0.33) was 12.005 msec (90% CI 4.412, 19.598) on day 28. For the 20-mg
treatment, the corresponding placebo-adjusted increase in the QTcF interval was 4.841 msec
(90% CI -4.009, 13.69) (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular; 8.2 Clinical Trial
Adverse Reactions, ECG Findings & 8.5 Post-Market Adverse Reactions; 9 DRUG
INTERACTIONS).
10.3 Pharmacokinetics
Absorption, Distribution, Metabolism, and Excretion:

Fluoxetine is well absorbed after oral administration. 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 PROZAC are bioequivalent. Food does
not appear to affect the systemic bioavailability of fluoxetine, although it may delay its
absorption inconsequentially. Thus, PROZAC may be administered with or without food.
Fluoxetine is extensively metabolized in the liver to norfluoxetine, and other unidentified
metabolites. The pharmacological activity of norfluoxetine, which is formed by demethylation
of fluoxetine appears to be similar to that of the parent drug. Norfluoxetine contributes to the
long duration of action of PROZAC. The primary route of elimination appears to be hepatic
metabolism to inactive metabolites excreted by the kidney. The elimination half -life of
fluoxetine is 4 to 6 days and that of its active metabolite is 4 to 16 days.
Clinical Issues Related to Metabolism/Elimination:

Variability in Metabolism:
The metabolism of fluoxetine, like that of a number of other compounds, including tricyclic
antidepressants and some selective serotonin reuptake inhibitors (SSRIs), involves the
P4502D6 system. Concomitant therapy with fluoxetine and the aforementioned drugs may
lead to clinically significant drug interactions (see 9 DRUG INTERACTIONS section).
Accumulation and Slow Elimination:

The relatively slow elimination of fluoxetine and its active metabolite, norfluoxetine, results in
significant accumulation of these active moieties in chronic use. Therefore, it may take up to 1
to 2 months for the active drug substance(s) to disappear from the body. This persistence of
active moieties is important to keep in mind when PROZAC is discontinued, or when drugs that
are predicted to interact with PROZAC are to be administered soon after its discontinuation
(see 7 WARNINGS AND PRECAUTIONS, General, Implications of the Long Elimination Half -Life
of Fluoxetine; and 9 DRUG INTERACTIONS sections).
Kinetic Data:
After 30 days of dosing at 20 mg/day, mean plasma concentrations of fluoxetine 79.1 ± 33.4
ng/mL and of norfluoxetine 129 ± 42.0 ng/mL have been observed. Plasma concentrations of
fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after
chronic administration) were higher than those predicted by single-dose studies. Norfluoxetine
appears to have linear pharmacokinetics. Its mean terminal half-lives after a single dose and
multiple doses were 8.6 days and 9.3 days, respectively.
Steady state plasma levels are attained after 4 to 5 weeks of continuous drug administration.
Patients receiving fluoxetine at doses of 40 to 80 mg/day over periods as long as 3 years
exhibited, on average, plasma concentrations similar to those seen among patients treated for
4 to 5 weeks at the same dose.
Protein Binding:
Approximately 94% of fluoxetine is protein bound. The interaction between fluoxetine and
other highly protein bound drugs has not been fully evaluated, but may be important (see 9
DRUG INTERACTIONS section).

Special Populations and Conditions
 Geriatrics: The effects of age upon the metabolism of fluoxetine have been
investigated in a subset of 260 elderly, but otherwise healthy, depressed patients
(mean age: 67.4 yr, range 60 to 85 yr) who received 20 mg PROZAC for 6 weeks. Mean
plasma concentrations were found to be 89.5 ± 53.6 ng/mL for fluoxetine and 119 ±
51.3 ng/mL for norfluoxetine. However, the effects of concomitant illness and/or
concomitant drugs have not been evaluated.
 Hepatic Insufficiency: In patients with cirrhosis, the elimination half -life of fluoxetine
was prolonged, with a mean of 7.6 days compared to a range of 2 to 3 days seen in
healthy subjects; norfluoxetine half-life was also prolonged, with a mean of 12 days
compared to a range of 7 to 9 days in healthy subjects. Fluoxetine should therefore be
used with caution in patients with liver disease (see 4.2 Recommended Dose and
Dosage Adjustment, Special Patient Populations; and 7 WARNINGS AND PRECAUTIONS,
Hepatic sections).
 Renal Insufficiency: In single dose studies, the pharmacokinetics of fluoxetine and
norfluoxetine were similar among subjects with all levels of impaired renal function
including anephric patients on chronic hemodialysis. However, with chronic
administration, additional accumulation of fluoxetine or its metabolites (possibly
including some not yet identified) may occur in patients with severely impaired renal
function, and the use of a lower or less frequent dose is advised (see 4.2
Recommended Dose and Dosage Adjustment, Special Patient Populations; and 7
WARNINGS AND PRECAUTIONS, Renal sections).
11 STORAGE, STABILITY AND DISPOSAL
Store PROZAC capsules at 15°-30°C.

Keep out of reach and sight of children.
12 SPECIAL HANDLING INSTRUCTIONS
Not applicable.

PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Fluoxetine hydrochloride
Chemical name: (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)-oxy]-propylamine
hydrochloride
Molecular formula and molecular mass: C17H18F3NO ● HCl
345.79
Structural formula:
Physicochemical properties:
Description: Fluoxetine is white to off-white crystalline solid.
pKa: 9.5 (66% Dimethylformamide)
Solubility Solvent mg/mL

Profile: Water 14
Benzene insoluble
Ethyl Acetate insoluble
14 CLINICAL TRIALS
14.1 Trial Design and Study Demographics
Depression
 The efficacy of PROZAC was established in 5- and 6- week placebo-controlled clinical
trials in depressed outpatients (≥ 18 yr of age), who meet the DSM-III-R criteria for
major depressive disorder.
 Two, 6-week placebo-controlled clinical trials in depressed elderly patients, who met
the DSM-III-R criteria for major depressive disorder (mean age 67.4 yr, range 60 to 85
yr) have shown PROZAC, 20 mg/day, to be effective.

 A study was conducted involving depressed outpatients who had responded (modified
HAMD-17 score of ≤ 7 during each of the last 3 weeks of open-label treatment and
absence of major depression by DSM-III-R criteria) by the end of an initial 12-week
open treatment phase on PROZAC 20 mg/day. These patients (N = 298) were
randomized to continuation on double- blind PROZAC 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 depression for 2 weeks or a modified
HAMD-17 score of ≥ 14 for 3 weeks) was observed for patients taking PROZAC
compared to those on placebo.
14.2 Study Results
See Section 14.1. Trial Design and Study Demographics.
16 NON-CLINICAL TOXICOLOGY
General Toxicology:
Subchronic/Chronic/Carcinogenicity and Related Toxicity Studies:
Subchronic Toxicity Studies
Mice were maintained for three months on diets equivalent to ca. 2, 7 or 31 mg/kg/day.
Significant effects were essentially limited to high dose mice and included 15% mortality;
persistent hyperactivity and decreased body weight gain; slight and reversible increases in
alkaline phosphatase and alanine transaminase; decreases in testes, heart, and spleen
weights; hypospermatogenesis; reversible pulmonary phospholipidosis.
Pulmonary histiocytosis (phospholipidosis) was the major pathological finding in rats
maintained on diets providing average doses of approximately 9, 25 or 74 mg/kg/day for
three months. All animals at ca. 74 mg/kg/day died by week 8. Decreased food
consumption, weight loss, and hyperirritability were observed at ca. 25 and 74 mg/kg/day.
Dogs survived oral doses up to 20 mg/kg/day for three months with significant anorexia as
the major treatment-related effect. Significant accumulation of both fluoxetine and
norfluoxetine occurred in the plasma and tissues. Mydriasis and tremors were observed
during the first month.
Monkeys given 10 or 25 mg/kg/day p.o. for two weeks exhibited anorexia and weight loss.
One monkey at 25 mg/kg/day exhibited clonic convulsions after six doses. Accumulation of
fluoxetine and norfluoxetine was observed after multiple dosing and decreased
erythrocyte and white blood cell counts were observed.
Chronic Toxicity Studies

Fluoxetine was given daily to rats (25/sex/dose) for one year at dietary levels of ca. 0.5,
2.3 and 10.7 mg/kg/day. Physical signs of toxicity were limited to females at the high dose
level and consisted of anorexia, chromodacryorrhea and an unusual behaviour first noted
during the eighth month of treatment in which the animals walked on their toes with feet
extended and backs arched after they had been handled.
Evidence of phospholipidosis was obtained in the lung, liver and adrenal cortex of 24/40
animals at the high dose level and in one rat at the mid-dose level. Phospholipidosis was
reversible after two months' withdrawal from treatment. Minimal to slight fat deposition
in the liver was prevalent at the mid and high dose levels. Reversible, minimal
reticuloendothelial cell hyperplasia was present in the lymph nodes of the high dose level
animals.
Dogs (5/sex/dose) received daily oral doses of 1, 4.5, or 20 mg/kg (decreased to 10 mg/kg
after 6 months as three females died) of fluoxetine for one year. The toxic effects
observed in this study were similar to those of the subchronic study except that
phospholipidosis was seen after chronic administration in the lung, liver, adrenals, the
inner plexiform layer of the retina, lymph nodes, spleen, and peripheral leukocytes in the
animals receiving the high dose. They also showed moderate bradycardia and a moderate
decrease in adrenal weight.
Phospholipidosis was only observed in the lung and leukocytes in a few of the dogs at the
lowest dose level of 1.0 mg/kg/day. No cardiovascular effects were seen apart from a
slight decrease in basal heart rate. All treatment-related effects were reversible during the
recovery period in surviving animals.
Discussion on Phospholipidosis: Systemic phospholipidosis was associated with the
subchronic and/or chronic administration of fluoxetine to mice, rats and dogs. This effect
was associated with the accumulation of norfluoxetine, and to a lesser extent, fluoxetine,
in affected tissues. Systemic phospholipidosis was not associated with any adverse effects
and was shown to be reversible after the chronic administration of fluoxetine for one year
in rats and dogs.
This effect has been demonstrated in animals with a number of other clinically useful
cationic amphiphilic drugs including antidepressants - imipramine, clomipramine, iprindole
and other drugs - chlorphentermine, fenfluramine, clozapine, chloroquine, mepacocine,
chlorcyclizine, tamoxifen, 4,4'diethylaminoethoxyhexestrol, amiodarone and perhexiline.
The significance of this finding for man is not fully understood. It is anticipated that in t he
clinical use of fluoxetine, the properties of the drug which are associated with
phospholipidosis will not result in any untoward effect.
Carcinogenicity:
Rats were maintained for two years at dietary levels equivalent to a time-weighted average
dose of ca. 0.45, 2 and 9 mg/kg/day. Age-related observations such as chromodacryorrhea,
alopecia, and poor grooming increased at the high dose, especially in females. Weight gain and
food consumption were depressed at the high dose and a handling-induced behaviour
involving arching of the back and walking on toes was observed primarily in females in this
group. Increased tissue levels of fluoxetine and norfluoxetine were observed at all doses, and
phospholipidosis was observed primarily at the high dose. There were no significant increases
in tumor incidence or animal mortality.

Mice were fed dietary levels of fluoxetine equivalent to ca. 1.2, 4.8 and 12.1 mg/kg/day. The
dietary levels were based on the results of the three-month subchronic study. Unexpectedly,
high mortality occurred in females receiving the high dose early in the two-year study,
necessitating lowering the dose after 30 days. The survival rate of females receiving the high
dose was reduced at two years. No major toxicological effects were seen in mice other than a
moderate increase in alanine transaminase in males receiving the high dose and slight changes
in organ weights. Hepatocellular degeneration, fat deposition in liver, and centrilobular
hepatocellular degeneration were observed microscopically at the median and high dose.
There was no evidence of phospholipid accumulation in the lung, and no oncogenic response
was observed.
A second two-year mouse study using similar doses gave similar results. Survival at two years
was reduced in females receiving the high dose. Handling-induced clonic convulsions occurred
at all levels in males, and in females, at the high-dose level it was accompanied by a slight
increase in liver weight. Minimal-to-moderate fatty change in the liver and hepatocellular
cytomegaly were seen in mice from the median- and high-dose levels. There was a dose-
dependent increase in concentrations of fluoxetine and norfluoxetine in lung tissue. There was
no evidence of phospholipid accumulation in the lung, and no oncogenic response was
observed.
Genotoxicity:
The mutagenicity of fluoxetine and its metabolite norfluoxetine was evaluated in a battery of
in vitro and in vivo tests including Ames test, modified Ames test, DNA repair in rat
hepatocytes, sister chromatid exchange in Chinese hamster bone marrow assays, and mouse
lymphoma assay. Fluoxetine and norfluoxetine were negative in all 5 systems.
Reproductive and Developmental Toxicology:

Reproductive and Impairment of Fertility Studies
Female Wistar rats (30/dose) were given daily oral doses of 2, 5, or 12.5 mg/kg from two
weeks prior to mating through gestation or lactation. In a second study, male Wistar rats
(40/dose) were maintained on diets approximately equivalent to 1.5, 3.9, or 9.7 mg/kg for 10
weeks prior to mating and through the breeding trial. These treated males were mated with
female Wistar rats (40/dose) maintained at the same dietary levels for three weeks prior to
mating and throughout lactation. In both studies, a depression in neonatal survival was
obtained at the high dose level. No teratogenic effects or adverse effects on fertility or post-
natal development were associated with fluoxetine administration.
Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5
times the MRHD on a mg/m2 basis) was not observed
In a juvenile toxicology study, fluoxetine hydrochloride was administered orally to CD rats
(30/sex/group) at doses of 0, 3, 10, and 30 mg/kg/day from postnatal days 21 through 91 and
evaluated for general clinical observations. Ten rats/sex/group were necropsied on postnatal
day 91 and evaluated for changes in clinical chemistry, hematology, femur length, organ
weights, and histopathology. Following an approximately 11-week recovery period, sperm

assessments were performed in all groups, and microscopic examination of testis and
epididymides occurred in the 30 mg/kg/day males only.
Plasma levels achieved at 30 mg/kg/day were approximately 5 to 8 fold (fluoxetine) and 18 to
20 fold (norfluoxetine), and at 10 mg/kg approximately 2 fold (fluoxetine) and 8 fold
(norfluoxetine) higher compared to plasma concentrations usually achieved in pediatric
patients.
Administration of 30 mg/kg/day of fluoxetine hydrochloride on postnatal days 21 through 90
resulted in a substantial decrease in body weight gain with concomitant degeneration and
necrosis of seminiferous tubules of the testis, epididymal epithelial vacuolation, epididymal
sperm granuloma, and immaturity and inactivity of the female reproductive tract.
Findings following an approximately 11-week recovery period in male rats administered 30
mg/kg/day, consisted of testicular degeneration, seminiferous tubular sperm
microgranulomas, epididymal epithelial cribriform change, epididymal epithelial vacuolation
and epididymal sperm granulomas. All of the rats with cribriform change had testicular
degeneration, and comparison to the treatment-phase rats indicted that the testicular
degeneration was irreversible. In contrast, the reduction in degree and extent of epididymal
vacuolation compared to the treatment-phase rats indicates that the vacuolation was
reversible.
Sperm assessments in the 30-mg/kg males only indicated an approximately 30% decrease in
sperm concentrations without affecting sperm morphology or motility. Decreased fertility was
observed in this dose-group. Delays in sexual maturation occurred in the 10 -mg/kg/day males
and in the 30-mg/kg/day males and females. The significance of these findings in humans is
unknown.
Teratology Studies
Virgin female Fischer 344 rats (25/dose) were bred with untreated control males and were
given daily oral (gavage) doses of 2, 5, or 12.5 mg/kg/day fluoxetine on gestation days 6-15;
animals were evaluated on gestation day 20. Body weight gains and food consumption were
depressed at 12.5 mg/kg/day. Fluoxetine produced no teratogenic effects and no changes in
reproductive parameters.
Virgin female Dutch Belted rabbits (15/dose) were artificially inseminated with semen from
untreated control males and were given daily oral (gavage) doses of 2.5, 7.5, or 15 mg/kg/day
fluoxetine on gestation days 6-18; animals were evaluated on gestation day 28. Maternal
toxicity was demonstrated by depressed body weight gains and food consumption at all dose
levels in a dose-dependent manner. At the 15 mg/kg/day dose, two rabbits died and three
aborted.
Resorptions were also increased in this group. There was no evidence of a teratogenic effect.
Juvenile Toxicity:
In a juvenile toxicology study in CD rats, administration of 30 mg/kg of fluoxetine
hydrochloride on postnatal days 21 through 90 resulted in increased serum activities of
creatine kinase (CK) and aspartate aminotransferase (AST), which were accompanied

microscopically by skeletal muscle degeneration, necrosis and regeneration. Femur lengths at
30 mg/kg increased to a lesser extent compared with control rats. The dose of 30 mg/kg was
associated with severe toxicity in general and exceeded a maximum tolerated dose. Other
findings are discussed in the Reproductive and Impairment of Fertility Studies.
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,
ip) 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 basis.

PATIENT MEDICATION INFORMATION
READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

Pr
PROZAC ®
Fluoxetine Hydrochloride Capsules
Read this carefully before you start taking PROZAC and each time you get a refill. This leaflet is
a summary and will not tell you everything about this drug. Talk to your healthcare
professional about your medical condition and treatment and ask if there is any new
information about PROZAC.
What is PROZAC used for?

PROZAC is used to relieve your symptoms of:
 Depression (feeling sad, a change in appetite or weight, difficulty concentrating or sleeping,
feeling tired, headaches, unexplained aches and pain)
 Bulimia (an eating disorder where you force yourself to vomit after eating)
 Obsessive-compulsive disorder (recurrent and intrusive thoughts, feelings, ideas, or
sensations; recurrent pattern of behaviour, or unwanted thoughts or actions)
How does PROZAC work?

PROZAC belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs).
PROZAC is thought to wo by increasing the levels of a chemical in the brain called serotonin.
This helps to relieve your symptoms of depression, bulimia and/or obsessive-compulsive
disorder.
What are the ingredients in PROZAC?

Medicinal ingredients: fluoxetine hydrochloride.
Non-medicinal ingredients: benzyl alcohol, butyl paraben, carboxymethylcellulose sodium,
edetate calcium disodium, F D & C Blue No. 1, gelatin, iron oxide yellow, methyl paraben,
propyl paraben, silicone, sodium propionate, sodium lauryl sulfate, starch, and titanium
dioxide.
There is no gluten, lactose, sulfite, or tartrazine in PROZAC.
PROZAC comes in the following dosage forms:

Capsules; 10 mg and 20 mg

Do not use PROZAC if:
 you are allergic to fluoxetine hydrochloride or to any of the non-medicinal ingredients
in PROZAC (see What are the ingredients in PROZAC:).
 you are currently or have recently taken the drug thioridazine.
 you are currently or have recently taken any monamine oxidase anti-depressants such
as phenelzine sulphate, moclobemide, linezolid. If you are unsure, ask your healthcare
professional.
To help avoid side effects and ensure proper use, talk to your healthcare professional before
you take PROZAC. Talk about any health conditions or problems you may have, including if
you:
 have anorexia
 have bipolar disorder
 have ever had an allergic reaction to any medication
 have QT/QTc prolongation or a family history of QT/QTc prolongation
 have a heart disease
 have a personal history of fainting spells
 have a family history of sudden cardiac death at less than 50 years of age
 have electrolyte disturbances (e.g., low blood potassium or magnesium levels) or
conditions that could lead to electrolyte disturbances (e.g., vomiting, diarrhea,
dehydration)
 have or have a history of a bleeding disorder or have been told that you have low
platelets
 have or have a history of liver or kidney problems
 have or have a history of seizures
 have diabetes
 had a recent bone fracture or were told you have osteoporosis or risk factors for
osteoporosis
 are pregnant, thinking about becoming pregnant, or if you are breast feeding
 drink alcohol and /or use street drugs
Other warnings you should know about:

During treatment with PROZAC, it is important that you and your doctor talk regularly about
how you are feeling.
Do NOT stop taking PROZAC without talking to your healthcare professional first, as it may
cause unwanted side effects such as headache, insomnia, numbness, tingling, burning, or
prickling, nervousness, anxiety, nausea, sweating, dizziness, jitteriness and weakness.

New or worsened emotional or behavioural problems: When you first start taking PROZAC or
when your dose is adjusted, you may feel worse instead of better. You may feel new or
worsened feelings of agitation, hostility, anxiety, or impulsivity, Do NOT stop taking your
medicine, it takes time for PROZAC to work.
Self-harm: If you have thoughts of harming or killing yourself at any time, contact your doctor
or go to a hospital right away. You may find it helpful to tell a relative or close friend that you
are depressed or have other mental illnesses. Ask them to read this leaflet. You might ask
them to tell you if they:
 think your depression or mental illness is getting worse, or
 are worried about changes in your behaviour
Pregnancy: Only take PROZAC during pregnancy if you and your doctor have discussed the
risks and have decided that you should. If you take PROZAC near the end of your pregnancy,
you may be at a higher risk of heavy vaginal bleeding shortly after birth. If you become
pregnant while taking PROZAC, tell your doctor right away.
Effects on newborns: In some cases, babies born to a mother taking PROZAC during pregnancy
may require hospitalization, breathing support and tube feeding. Be ready to seek medical
help for your newborn if they:
 Have trouble breathing or feeding,
 Have muscle stiffness, or floppy muscles (like a rag doll)
 Have seizures (fits)
 Are shaking (jitteriness)
 Are constantly crying
If you take PROZAC:

 During early pregnancy, there is a possible slight increased risk that your newborn may
have a heart defect.
 During late pregnancy, your newborn may be at risk of having a serious lung condition
called Persistent Pulmonary Hypertension of the Newborn (PPHN), which causes
breathing problems.
Falls: PROZAC can cause you to feel sleepy or dizzy and can affect your balance. This increases
your risk of falling, which can cause fractures or other fall related-injuries, especially if you:
 Take sedatives
 Consume alcohol
 Are elderly
 Have a condition that causes weakness or frailty
Driving and using machines: PROZAC may make you feel sleepy. Give yourself time after
taking PROZAC to see how you feel before driving a vehicle or using machinery.

PROZAC can cause serious side effects including:
 Angle-closure glaucoma (sudden eye pain)
 Heart rhythm problems
See the Serious side effects and what to do about them table below for more information
on these and other serious side effects.
Tell your healthcare professional about all the medicines you take, including any drugs,
vitamins, minerals, natural supplements or alternative medicines.
The following may interact with PROZAC:
Serious Drug Interactions

Do not use PROZAC if you are taking or have recently taken:
• Monoamine oxidase inhibitor (e.g., phenelzine, tranylcypromine, moclobemide or
selegiline, linezolid, methylene blue)
• Thioridazine
 drugs that affect how your heart beats such as quinidine, procainamide, disopyramide,
amiodarone, sotalol, ibutilide, dronedarone, flecainide, propafenone
 drugs used to manage psychosis (antipsychotics) such as chlorpromazine, pimozide,
haloperidol, droperidol, ziprasidone, clozapine
 drugs used to treat depression such as citalopram, venlafaxine, amitriptyline,
imipramine, maprotiline, desipramine
 opioids and pain killers such as methadone, tramadol, fentanyl, tapentadol,
meperidine, pentazocine
 drugs to treat bacterial infections such as erythromycin, clarithromycin, telithromycin,
tacrolimus, moxifloxacin, levofloxacin, ciprofloxacin
 drugs used to treat fungal infections such as ketoconazole, fluconazole, voriconazole
 drugs used to treat malaria such as quinine, chloroquine
 drugs used to treat nausea and vomiting such as domperidone, dolasetron,
ondansetron
 drugs used in cancer therapy such as vandetanib, sunitinib, nilotinib, lapatinib,
vorinostat, tamoxifen
 drugs used to treat asthma such as salmeterol, formoterol
 drugs that affect your electrolyte levels such as diuretics (“water pills”), laxatives and
enemas, amphotericin B, high dose corticosteroids (drugs that reduce inflammation)
 drugs that can affect how your blood clots such as warfarin, acetylsalicylic acid
(Aspirin), non-steroidal anti-inflammatory drugs (NSAIDs)
 lithium, a drug used to treat bipolar disorder
 benzodiazepines such as diazepam, alprazolam
 drugs used to treat seizures such as carbamazepine, phenytoin

 drugs used to treat cough such as dextromethorphan
 tryptophan, a drug used to treat anxiety or used as a sleep aid
 sumatriptan, a drug used to treat migraines
 herbal medicines such as St. John’s Wort
 alcohol
How to take PROZAC:

 It is very important that you take PROZAC exactly as your doctor has instructed.
 PROZAC may be taken with or without food.
 Swallow the capsules whole; do not chew or open them.
 Continue to take your medicine even if you do not feel better, as it may take a number
of weeks for your medicine to start working.
 Keep taking your PROZAC until the doctor tells you to stop.
Remember, this medicine has been prescribed only for you. Do not give it to anybody else,
as they may experience undesirable effects, which may be serious.
Usual dose:
Depression
Usual initial dose: 20 mg a day in the morning. Maximum dose: 60 mg a day.
Bulimia
60 mg a day.
Obsessive-Compulsive Disorder
20 mg to 60 mg a day.
Overdose:
If you think you, or a person you are caring for, have taken too much PROZAC, contact a
healthcare professional, hospital emergency department, or regional poison control centre
immediately, even if there are no symptoms.
Missed Dose:
If you forget to take a dose of PROZAC, take it as soon as you remember. If it is almost time to
take your next dose, skip the missed dose and take your next dose at the scheduled time. Do
not try to make up for a missed dose by taking a double dose the next time.

What are possible side effects from using PROZAC?
These are not all the possible side effects you may have when taking PROZAC. If you
experience any side effects not listed here, tell your healthcare professional.
 nausea
 dizziness
 headache
 anxiety
 nervousness
 drowsiness
 insomnia (difficulty falling or staying asleep)
 fatigue
 weakness
 tremors (shaking)
 light-headedness
 diarrhea
 upset stomach
 indigestion
 dry mouth
 loss of appetite
 excessive sweating
 rash or itchy skin
 low sex drive
 weight gain or loss
Serious side effects and what to do about them

Talk to your healthcare professional Stop taking drug and
Symptom / effect get immediate
Only if severe In all cases
medical help
COMMON
Allergic Reaction: difficulty
swallowing or breathing, wheezing,
feeling sick to your stomach and 
throwing up, hives or rash, swelling
of the face, lips, tongue or throat.
Allergic reactions (skin rash, hives

alone)
Anorexia (an eating disorder):
extremely low body weight, not
eating, obsession with food, 
calories and dieting, excessive
exercise

UNCOMMON 
Akathisia (a type of movement
disorder): feeling restless, unable 
to sit or stand still
Hallucinations (seeing or hearing

things that are not there)
Mania: elevated or irritable mood,
decreased need for sleep, racing 
thoughts
Seizures (fits): uncontrollable
shaking with or without loss of  
consciousness
Urinary retention (inability to pass
urine or to empty the bladder): 
pain
RARE
Angle-closure glaucoma (sudden
eye pain): increased pressure in
your eyes, eye and head pain,

swelling or redness in or around
the eye, hazy or blurred vision,
sudden loss of sight
Gastrointestinal Bleeding
(bleeding in the stomach or
 
bowels): black, tarry stool, blood in
the stool
Heart rhythm problems: dizziness,
palpitations (rapid, pounding, or
 
irregular heartbeat), fainting or
seizures
Hyponatremia (low sodium in the
blood): lethargy, confusion,
muscular twitching, achy, stiff or  
uncoordinated muscles, seizure,
coma
Liver Disorder: yellowing of the
skin or eyes, dark urine and pale
 
stools, abdominal pain, nausea,
vomiting, loss of appetite
Uncontrollable movements of the
 
body or face
VERY RARE
Serotonin Syndrome: agitation,
hallucinations, confusion, or other
changes in mental status; 
coordination problems,
uncontrolled muscle spasms, or

muscle twitching (overactive
reflexes); restlessness, shivering,
racing or fast heartbeat, high or
low blood pressure, sweating or
fever, nausea, vomiting, or
diarrhea, stiff muscles, tremor, loss
of muscle control
UNKNOWN  
Increase in the hormone prolactin:
In women: breast discomfort,
leakage of milk from the breasts,
missed periods, or other problems
with your menstrual cycle.  
In men: decreased body and facial
hair, breast swelling, difficulty in
getting or maintaining erections, or
other sexual dysfunction
New or worsened emotional or
 
behavioural problems
Thrombocytopenia (low blood
platelets): bruising or bleeding for
 
longer than usual if you hurt
yourself, fatigue and weakness
If you have a troublesome symptom or side effect that is not listed here or becomes bad
enough to interfere with your daily activities, tell your healthcare professional.
Reporting Side Effects
You can report any suspected side effects associated with the use of health products to
Health Canada by:
 Visiting the Web page on Adverse Reaction Reporting

https://www.canada.ca/en/health-canada/services/drugs-health-
products/medeffect-canada/adverse-reaction-reporting.html) for information on how
to report online, by mail or by fax; or
 Calling toll-free at 1-866-234-2345.
NOTE: Contact your health professional if you need information about how to manage your
side effects. The Canada Vigilance Program does not provide medical advice.

Storage:
 Store PROZAC in its original package at room temperature (15°C to 30°C), in a dry place
and out of direct sunlight.
 Do not use the medicine after the expiry date printed on the package label.
 If your doctor tells you to stop taking PROZAC or you find that the capsules have passed
their expiry date, please return any left over medicine to your pharmacist.
Keep out of reach and sight of children.
If you want more information about PROZAC:

 Talk to your healthcare professional
 Find the full product monograph that is prepared for healthcare professionals and
includes this Patient Medication Information by visiting the Health Canada website:
(https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-
products/drug-product-database.html; the manufacturer’s website www.lilly.ca, or by
calling 1-888-545-5972.
PROZAC ® (fluoxetine hydrochloride) is a trademark owned or licensed by Eli Lilly and
Company, its subsidiaries or affiliates.
This leaflet was prepared by Eli Lilly Canada Inc.
Last Revised July 13, 2021
PROZAC-CA-PM- 0003-20210713

Prozac CA PM

Uploaded by

Copyright:

Available Formats

Prozac CA PM

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Prozac CA PM

Uploaded by

Copyright:

Available Formats

PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

© Eli Lilly Canada Inc. Date of Initial Authorization:

Submission Control Number: 249549

PROZAC (fluoxetine hydrochloride) Page 1 of 51

7 Warnings and Precautions 07/2021

PROZAC (fluoxetine hydrochloride) Page 2 of 51

PROZAC (fluoxetine hydrochloride) Page 3 of 51

PROZAC (fluoxetine) is indicated in adults for:

 Hypersensitivity - PROZAC is contraindicated in patients who are hypersensitive to this

PROZAC (fluoxetine hydrochloride) Page 4 of 51

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Switching Patients to a Tricyclic Antidepressant (TCA):

Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI):

PROZAC (fluoxetine hydrochloride) Page 5 of 51

4.2 Recommended Dose and Dosage Adjustment

PROZAC (fluoxetine hydrochloride) Page 6 of 51

4.5 Missed Dose

Signs and Symptoms:

PROZAC (fluoxetine hydrochloride) Page 7 of 51

PROZAC (fluoxetine hydrochloride) Page 8 of 51

PROZAC (fluoxetine hydrochloride) Page 9 of 51

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Route of Dosage Form /

There is no gluten, lactose, sulfite, or tartrazine

Availability of Dosage Forms:

7 WARNINGS AND PRECAUTIONS

Pediatrics - Placebo-Controlled Clinical Trial Data

Adults and Pediatrics - Additional data

PROZAC (fluoxetine hydrochloride) Page 10 of 51

Implications of the Long Elimination Half-Life of Fluoxetine

Use of PROZAC in Pregnant Women: Effects on Newborns

Carcinogenesis and Mutagenesis:

PROZAC (fluoxetine hydrochloride) Page 12 of 51

Driving and Operating Machinery

PROZAC (fluoxetine hydrochloride) Page 13 of 51

PROZAC (fluoxetine hydrochloride) Page 14 of 51

PROZAC (fluoxetine hydrochloride) Page 15 of 51

PROZAC (fluoxetine hydrochloride) Page 16 of 51

PROZAC (fluoxetine hydrochloride) Page 17 of 51

Reproductive Health: Female and Male Potential

7.1 Special Populations

7.1.1 Pregnant Women

Pregnant Women and Newborns

Possible Risk of Cardiovascular Malformations following first trimester exposure to SSRIs

Complications following late third trimester exposure to SSRIs

Risk of PPHN and exposure to SSRIs (including fluoxetine)

PROZAC (fluoxetine hydrochloride) Page 19 of 51

8.1 Adverse Reaction Overview

Commonly Observed Adverse Events

PROZAC (fluoxetine hydrochloride) Page 20 of 51

8.2 Clinical Trial Adverse Reactions

PROZAC (fluoxetine hydrochloride) Page 21 of 51

PROZAC (fluoxetine hydrochloride) Page 22 of 51

Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more patients

PROZAC (fluoxetine hydrochloride) Page 23 of 51

Table 4: Adverse Events Associated with Discontinuation of PROZAC Treatment

Male and Female Sexual Dysfunction with SSRIs: