Review

General

Safety and side effect profile of

fluoxetine
Joachim F Wernicke
1. Introduction Lilly Corporate Center, Indianapolis, IN 46285, USA
2. Methods
Fluoxetine was the first selective serotonin re-uptake inhibitor to be widely
3. Results
available for treatment of depression and numerous other neuropsychiatric
4. Expert opinion and conclusion disorders. Its attributes have been described in numerous scientific papers,
and it has been the subject of a considerable volume of lay press. Fluoxetine
is generally safe and well-tolerated. Common adverse events reported with
the recommended dose of 20 mg/day are referable to the gastrointestinal
system and the nervous system. The approved dose range is up to 80 mg/day,
and when higher doses are used, adverse events are more common. The long
half-life of fluoxetine and its active metabolite essentially preclude a with-
drawal phenomenon. It is an inhibitor of cytochrome P450 (CYP) 2D6 and
other CYP enzymes, which increases the potential for drug interactions. How-
ever, most of these are not clinically important. The purpose of this review is
to provide an overview of some of the most important information related to
safety and side effects of this drug.

Keywords: fluoxetine, Prozac, safety, side effects

Expert Opin. Drug Saf. (2004) 3(5):495-504

1. Introduction

Fluoxetine (Prozac, Eli Lilly & Co.) was the first selective serotonin re-uptake
inhibitor (SSRI) to be approved in the USA. Since FDA approval in 1987, it has
been used by millions of patients worldwide, and has been the subject of extensive
literature, both scientific and lay. A Medline search for fluoxetine, conducted in
April 2004, yielded 5832 citations.
Developing a drug that is first-in-class provides the manufacturer with many
advantages, but also creates considerable anxiety on the part of regulators, the medi-
cal community, the public (including patients) and the manufacturer. This is
because there is no experience with this class of drug. In the case of fluoxetine, a
heightened sense of anxiety was created by zimeledine, which had been approved in
Europe, but was withdrawn due to postmarketing reports of a flu-like syndrome,
which was rarely associated with GuillianBarr syndrome. This rare idiosyncratic
reaction appears to be related to the chemical structure of zimeledine, as fluoxetine
and other SSRIs are not associated with such a syndrome [1].

2. Methods
For reprint orders, please
contact:
reprints@ashley-pub.com This review is based on published literature generated by a Medline search. Articles,
the titles of which suggested that they focused on safety issues, were selected for fur-
ther consideration and are reviewed here. Rather than citing every report in the
extensive fluoxetine literature, articles were chosen for their heuristic value. Case
reports are discussed only if they are of particular interest. Comparisons to other
drugs are made only if absolutely necessary.
Ashley Publications
www.ashley-pub.com Adverse event reporting frequencies were based on data reported by
Beasley et al. [2]. The authors reported rates of spontaneously reported (as opposed

2004 Ashley Publications Ltd ISSN 1474-0338 495

Safety and side effect profile of fluoxetine

to solicited events) adverse events for patients taking fluoxe- can be used safely in patients with panic disorder. A study of
tine and placebo in trials of patients taking fluoxetine at fluoxetine in patients with panic disorder indicates that the
doses ranging 20 80 mg/day, as well as for studies in which adverse event profile is similar to that in patients with
patients took only 20 mg/day. Frequencies from studies depression [7], again suggesting that the adverse event profile
in which fluoxetine 20 80 mg/day was given, as well as does not preclude usefulness of the drug in patients who suf-
for studies utilising fluoxetine 20 mg/day and the respective fer from, or are likely to develop, such complaints.
placebo rates, are shown in this review. To avoid having 3.1.1.2 Long-term treatment
to make comparison to two placebo rates (from studies Although individual depressive episodes may respond to
where fluoxetine was taken at doses of 20 80 mg/day and therapy fairly rapidly, it has become clear that even in these
20 mg/day), fluoxetine rates for the 20 mg/day studies were patients, longer-term therapy is crucial in order to prevent
also adjusted for placebo rates. This was done as follows: relapse. Conducting long-term placebo-controlled studies of
Fluoxetine (FLX)20adjusted = FLX20 observed * (Placebo depressed patients is difficult, although it has been accom-
[PBO]20 80/PBO20) where: plished, and efficacy of fluoxetine in relapse prevention has
been demonstrated [8,9]. Relapse prevention studies, in which
FLX20adjusted = the adjusted rate for patients taking
responders are randomised to continue on a drug or switch to
fluoxetine 20 mg/day
placebo, have provided comparative data on long-term ther-
FLX20observed = the observed rate for patients taking
apy in a controlled setting. Adverse events tend to occur
fluoxetine 20 mg/day
early, and do not usually appear during long-term therapy
PBO20 80 = the observed rate for patients taking pla-
[10]. In a 48-week study, Gilaberte et al. [11] found that
cebo in the studies where fluoxetine was taken at doses of
patients who switched from fluoxetine to placebo were more
20 80 mg/day
likely to report anxiety than those who continued on fluoxet-
PBO20 = the observed rate for patients taking placebo in
ine, but otherwise there were no statistically significant dif-
the studies where fluoxetine was taken at 20 mg/day.
ferences between groups.
During long-term therapy, the initial weight loss experi-
3. Results enced by many patients tends to subside, with mean weight
only slightly lower than when therapy was started [12,13]. In
3.1 Adverse event profile
some studies modest weight gain, associated with relief of
3.1.1 Common events
depression, has been reported [12].
3.1.1.1 Acute treatment
Reports of adverse events possibly associated with fluoxetine
3.1.2 Uncommon but important events
have appeared in numerous reports of clinical trials. The
3.1.2.1 Sexual dysfunction
first comprehensive review of fluoxetine over the dose range
Sexual desire is often inhibited in depressed patients [14],
20 80 mg/day first appeared in 1985 [1], and was updated in
which complicates assessment of drug effects. Nevertheless,
2000 with much larger numbers [2]. Adverse events reported
fluoxetine is known to delay time to orgasm in men and
by Beasley et al. for > 5% of patients taking fluoxetine at doses
women, and possibly to inhibit libido, but many patients
ranging 20 80 mg/day, adjusted as described above, are
develop tolerance to these effects [15]. Inhibition of orgasm is a
shown in Table 1. Common adverse events reported with the
property that has been exploited to treat men with premature
recommended dose of 20 mg/day are referable to the gastroin-
ejaculation [16]. In addition to disturbances of arousal and
testinal (GI) system (nausea, diarrhoea and anorexia) and the
orgasm, decreased sensation in primary and secondary sex
nervous system (insomnia, somnolence, anxiety and asthenia).
organs has been reported [17].
The approved dose range is up to 80 mg/day, and when 3.1.2.2 Mania and hypomania
higher doses are used, adverse events are more common. Induction of mania, especially in patients with undiag-
However, even the higher doses are quite well-tolerated, nosed bipolar disorder being treated for an episode of
including the 90 mg once-weekly formulation [3]. Adverse depression, is always of concern. Rates of mania or hypo-
events commonly associated with initiation of fluoxetine ther- mania during fluoxetine therapy are considered to be low,
apy tend to subside, and it was found that no adverse events and range 0 15%, depending on the type of patient and
reported initially became more frequent late in therapy [4]. duration of therapy [18]. Hypomania and exacerbation of
The advisability of whether or not to use a drug likely to behavioural abnormalities have been reported in patients
produce undesirable effects already suffered by the patient as with Aspergers syndrome [19]. Hypomania has also been
part of their disorder is relevant. Pretreatment insomnia and reported following a serotonin syndrome (discussed below)
anxiety did not influence the outcome of treatment with associated with concomitant use of fluoxetine and tramadol
fluoxetine [5], and fluoxetine used for treatment of patients [20]. Patients with bipolar disorder who have a deletion in
who suffered insomnia as part of their depression responded the promoter region of the gene that codes for the serot-
just as well to fluoxetine as those without insomnia [6]. Simi- onin transporter have been found to be particularly suscep-
larly, adverse events such as anxiety and nervousness may tible to mania [21], as well as insomnia and agitation [22].
raise questions as to whether or not drugs such as fluoxetine
496 Expert Opin. Drug Saf. (2004) 3(5)
 Wernicke

Table 1. Frequency of adverse events reported by patients taking fluoxetine*.

FLX20 80 PBO20 80 FLX20adjusted FLX20 PBO20

Nausea 21.6 9.0 17.6 16.8 8.6
Headache 17.7 18.2 18.0 20.9 21.1
Insomnia 16.3 9.0 13.3 15.1 10.2
Nervousness 13.7 8.8 10.4 10.6 9.0
Somnolence 12.8 6.0 10.6 7.8 4.4
Anxiety 12.1 6.9 9.5 12.8 9.3
Diarrhoea 11.9 7.2 11.1 13.2 8.6
Anorexia 11.4 2.3 9.1 9.9 2.5
Dry mouth 10.1 7.4 9.8 7.4 5.6
Tremor 9.8 3.5 5.1 5.4 3.7
Dizziness 9.4 7.1 8.0 9.1 8.1
Rhinitis 9.2 10.6 7.8 10.1 13.7
Asthenia 8.9 5.3 7.3 9.7 7.0
Sweating 8.6 3.5 6.9 6.5 3.3
Dyspepsia 7.0 4.6 6.7 7.4 5.1
Constipation 5.4 4.9 4.7 5.9 6.2
*At doses of 20 80 mg/day (FLX20 80), comparator rates for patients taking placebo (PBO20 80), rates for patients taking fluoxetine 20 mg/day, adjusted for
placebo rates in studies where the fluoxetine group took 20 mg/day (FLX20 adjusted), actual rates for fluoxetine (FLX20) and placebo (PBO20) from studies where
fluoxetine was given at a dose of 20 mg/day. Adapted from Beasley et al. [2].
Adverse events reported at frequencies statistically significantly greater by the fluoxetine groups than by the respective placebo group are indicated in bold.
FLX: Fluoxetine; PBO: Placebo.

3.1.2.3 Movement disorders and other neurological 3.1.2.4 Metabolic disturbances

disturbances Older patients are at increased risk for hyponatraemia and
As is true with many psychoactive drugs, including other SSRIs, syndrome of inappropriate secretion of antidiuretic hormone.
patients taking fluoxetine may experience myoclonic jerks [23], Use of fluoxetine has been associated with hyponatraemia in
but these movements usually occur when fluoxetine is taken in elderly patients, typically after 3 weeks of treatment, and is
conjunction with other drugs, and are not necessarily indicative more likely to occur in patients with low body weight [30].
of a serotonin syndrome [24], which is described below. 3.1.2.5 Cardiac effects
Akasthesia, often described as a feeling of inner restlessness, In clinical studies fluoxetine has been reported to be associ-
has also been reported in individual patients taking fluoxetine ated with a mean decrease in pulse of 5 beats/min [31]. How-
[25]. Although this term is often used, there seems to be little ever, no cardiac effects were found in carefully conducted
consistency in its definition. It has been suggested that the electrocardiographic studies [32].
psychomotor activation reported by patients taking fluoxetine Because prolongation of cardiac repolarisation, as measured
is related to effects on the dopaminergic system, a hypothesis by QT prolongation, may be associated with fatal arrhyth-
that has not been proven [26]. mias, drugs are being scrutinised with increasing intensity.
Individual cases of other extrapyramidal symptoms, includ- Fluoxetine has not been associated with QT prolongation [32],
ing Parkinsonism, tremor, dystonia, tardive dyskinesia, tics, although isolated reports to the contrary have appeared [33].
and chorea, have been reported, and are thought to result 3.1.2.6 Other
from an interaction between the serotonergic and dopaminer- Rare cases of neutropenia [34] and hepatitis [35] have been
gic systems [23]. This theory is supported by the finding that reported.
fluoxetine can reverse the therapeutic effects of levodopa in
some patients with dopa-responsive dystonia [27]. 3.2 Safety
As is true with most psychotropic drugs, seizures have been 3.2.1 Overdose
reported in patients taking fluoxetine. The reported rate is Compared to older antidepressants (tricyclic antidepressants
0.2%, but it is not clear that these seizures were related to [TCAs] and monamine oxidase inhibitors [MAOIs]), one of
fluoxetine, especially since the drug has been reported to have the major advantages of fluoxetine and other SSRIs is their
anticonvulsant properties [28]. Visual hallucinations have been relative safety in overdose. This is a major consideration for
reported in individual cases [29]. treatment of depressed patients, who are at high risk for

Expert Opin. Drug Saf. (2004) 3(5) 497

Safety and side effect profile of fluoxetine

suicide attempts, often with medications prescribed to treat 3.2.3.2 Geriatric

their depression [36]. SSRIs, in particular fluoxetine, are Depression in older patients is a serious problem, often end-
reported to be 10 100 times safer in overdose than TCAs, ing in suicide. Treatment of this patient population is
especially in regard to cardiac effects [36,37]. complicated by the fact that they tend to be in poorer health
and be taking multiple medications, which increases their risk
3.2.2 Suicidality of drug interactions. Fluoxetine has reported to be generally
Much has been said and written about the relationship well-tolerated in the elderly [62]. It may be associated with
between fluoxetine and suicide, both in the medical literature modest loss of weight, but this has not been found to be a
and the lay press. The issue was initially raised by a series of problem for older patients, for whom weight loss may be
anecdotal reports [38]. The same authors then proposed nine undesirable [63]. During long-term therapy, weight tends to
possible mechanisms to explain how fluoxetine may exacer- increase, and it is believed that this increase accompanies
bate suicidal tendencies [39]. Complicating an unprejudiced relief of depression [12].
analysis of this issue is the fact that patients most often treated 3.2.3.3 Pregnancy and lactation
with fluoxetine are depressed, and 15% of depressed Although it is prudent to avoid use of drugs during preg-
patients eventually commit suicide [40]. The issue is further nancy, this is not always possible. Fluoxetine crosses the pla-
complicated by selection bias in that patients at high risk for centa, with umbilical cord plasma concentrations being only
suicide [41] and those more severely depressed [42] tend to be slightly lower than those of the mother [64]. Data from
treated with fluoxetine, presumably because it is safer in over- > 3000 pregnancies indicates that there is no increased risk
dose then are older drugs, such as TCAs and MAOIs. of major congenital malformations in infants exposed to
Of issue is the question of whether or not fluoxetine can fluoxetine [65], although low birth weight has been reported
induce patients to commit suicide who would not have done in patients taking high doses of fluoxetine throughout the
so otherwise. Although some authors claim that there is evi- pregnancy [66], and signs suggestive of a serotonin syndrome
dence for such an association [43], analysis of epidemiological (especially restlessness, tremor, shivering and rigidity) have
data and a review of published literature, including reports of been observed in the first few days of life [67]. Perhaps more
clinical trials, have indicated no such relationship [44-52]. Fur- important are effects upon the development of children born
thermore, no relationship between fluoxetine and suicidality to mothers taking fluoxetine. Fluoxetine was found not to
was found in studies of other indications, including obsessive have adverse effects on childrens global IQ and language
compulsive disorder [53], bulimia nervosa [54] and obesity [55]. development of behavioural IQ [68]. Overall, fluoxetine is
This issue has recently re-emerged because of reports of sui- generally considered to be relatively safe in pregnancy, even
cidal ideation in adolescents taking SSRIs. As fluoxetine is the in the presence of renal failure [69].
only SSRI approved for treatment of depression in children in Like other psychotropic drugs, fluoxetine is excreted in
the US, the question of a link to suicidal behaviour deserves breast milk. Maternal milk and infant plasma concentrations
further consideration. The UK Committee on Safety of Med- are low, and usually not associated with noticeable effects in
icines has deemed fluoxetine the only SSRI with a favourable the infant [70], although colic, fussiness, crying, seizure activity
risk/benefit profile for treatment of adolescent depression, and reduced weight gain have been reported [71]. Although
and has contraindicated other SSRIs for this application [56], morbidity associated with postpartum depression is consider-
and the American College of Neuropsychopharmacology did able and fluoxetine appears to be safe, benefits relative to
not find an association between SSRIs and suicidality in ado- potential risks must be considered.
lescents [201]. Nevertheless, the potential link between SSRIs 3.2.3.4 Concomitant illnesses
and suicidal behaviour has prompted regulatory agencies in 3.2.3.4.1 Heart disease

the US and Europe to mandate class labelling, which warns Many depressed patients suffer from illness in addition to their
about this possibility. The actual data on which this warning depression, and these disorders require treatment at the same
is based have not been published. time that the depression is treated. Cardiac disease, especially
in older patients, is among the most common co-morbid dis-
3.2.3 Special populations and conditions orders with depression. In a series of 27 patients with conges-
3.2.3.1 Children and adolescents tive heart failure, conduction disease, and/or ventricular
Children develop steady-state plasma concentrations of arrhythmias, fluoxetine was found to be safe [72], and this was
fluoxetine and norfluoxetine that are approximately twice confirmed in a larger study of patients with congestive heart
those of adolescents, whose pharmacokinetic parameters are failure [31]. Fluoxetine, like other SSRIs, may actually decrease
similar to those of adults [57]. Nevertheless, fluoxetine is the risk of myocardial infarction due to its serotonin-depleting
generally well-tolerated in children and adolescents, with an effect on platelets [73]. Fluoxetine has no effect on blood pres-
adverse event profile similar to that of adults. Safety data sure, either in patients with hypertension or those who are nor-
have been reported for studies of numerous indications, motensive [74]. This does not mean that patients taking
including depression [58], anxiety [59] and obsessive-compul- fluoxetine may not experience cardiac and other events.
sive disorder [60,61]. Indeed, the package insert lists many treatment-emergent

498 Expert Opin. Drug Saf. (2004) 3(5)

 Wernicke

events (first appeared or worsened during therapy). This does St Johns wort is becoming an increasingly popular herbal
not mean that they were caused by the drug, only that they preparation used for self-medication of depression.
first appeared during the study. Proximity does not prove, or Unfortunately, some patients do not consider it as a drug and
even imply, causality. However, infrequent events cannot be fail to mention it when being prescribed an antidepressant.
discounted as unrelated to drug. It is only with the collection St Johns wort contains many pharmacologically active com-
of more data that causal relationships can be determined. pounds, and is capable of inhibiting synaptic serotonin re-
3.2.3.4.2 Stroke uptake [83]. When given with fluoxetine, a serotonergic syn-
Stroke is often followed by depression. Fluoxetine was found drome can ensue, a problem that is compounded by inhibi-
to be safe in this population, and in fact, has been reported to tion of CYPs that metabolise the active ingredient [84].
decrease mortality in patients who have suffered a stroke, 3.2.4.2 Non-serotonergic drugs and therapies
regardless of whether or not they are depressed [75]. Patients with complex neuropsychiatric disorders often require
3.2.3.4.3 Diabetes combination therapy, especially with antipsychotics. The com-
Depression is a common co-morbid condition with diabetes. bination of fluoxetine and olanzapine has been studied exten-
Fluoxetine is generally well-tolerated by diabetic patients and sively, and found to be well-tolerated [85]. In fact, this
may actually improve peripheral insulin resistance. The package combination has been marketed under the name of Symbyax
insert cautions that insulin doses may need to be adjusted. A case (Eli Lilly & Co.). Although the fluoxetine package insert cau-
of loss of hypoglycaemic awareness (hunger, diaphoresis and gen- tions that ECT-induced seizures may be prolonged, there is lit-
eralised weakness) while taking fluoxetine has been reported [76]. tle evidence that that this is a problem in clinical practice [86].
3.2.3.4.4 Cancer The concomitant use of oral contraceptives and fluoxetine
Treatment of depression in cancer patients is often complicated has been reported to be safe, with neither drug having a sub-
by the compromised health of these patients and increased stantial effect on the other [87].
potential for drug interactions during cancer therapy. Fluoxet- Excessive bleeding has been reported in patients receiving
ine has been found to be generally well-tolerated in a popula- heparin for anticoagulation [88]. Presumably this is the result
tion of patients suffering from cancer as well as depression [77]. of fluoxetine-associated depletion of platelet serotonin, lead-
ing to platelet dysfunction. Under normal circumstances, this
3.2.4 Drug and other interactions is generally of no consequence. An interaction with warfarin,
3.2.4.1 Serotonin effects manifest as increased anticoagulation, has been reported [89],
Fluoxetine and other SSRIs lead to an increase in serotonin although the hypoprothrombonaemic response of warfarin
through the inhibition of serotonin transport mechanisms. was found not to be altered by fluoxetine [90]. Given the dire
An excessive elevation of serotonin, usually the result of taking consequences of over-anticoagulation, caution is advised.
more than one serotonergic drug, may lead to what is termed Fluoxetine is a potent inhibitor of CYP2D6, which is an
a serotonin syndrome. Signs of the serotonin syndrome important enzyme in the metabolism of 30% of all drugs
include mental status changes (confusion, hypomania), agita- [62]. Thus, plasma concentrations of drugs metabolised by
tion, myoclonus, muscle rigidity (usually lower extremity pre- CYP2D6 are the most likely to be altered by fluoxetine. Due
dominating), hyperreflexia, diaphoresis, shivering, tremor, to relatively wide margins of safety, these changes are not clin-
diarrhoea, incoordination and fever. However, not all of these ically relevant for many drugs, and dangerous drug interac-
are required to make the diagnosis [78], and other signs includ- tions between fluoxetine and other drugs are reported to be
ing apnoea, coma and flaccid paralysis, have been reported rare [91]. CYP3A4 is weakly inhibited by fluoxetine, but
[79]. In severe cases of serotonin syndrome, deaths have been important interactions are less likely than with drugs metabo-
reported, which is why most SSRIs, including fluoxetine, are lised by CYP2D6. Drugs metabolised by these enzymes may
contraindicated with MAOIs. be used in conjunction with fluoxetine, but additional precau-
The nonspecific MAOIs are irreversible inhibitors of the tions must be taken, and sometimes monitoring of plasma
enzyme, requiring 2 weeks before new molecules are synthe- concentrations and dose adjustments are advisable. Examples
sised. Thus, fluoxetine should not be given within 2 weeks of of some of the more important drug interactions related to
discontinuation of an MAOI. Due to the long half-life of CYP inhibition are given in Table 2. This list is given as an
fluoxetine (3 4 days), and the even longer half-life of its example, and should not be considered to be exhaustive.
active metabolite, norfluoxetine (1 2 weeks), MAOIs should Comprehensive and up-to-date information on drug interac-
not be given until 5 weeks (5 half-lifes) after fluoxetine has tions can be found online [202].
been discontinued.
Use of other drugs in conjunction with fluoxetine has been 3.2.5 Drug withdrawal
reported to result in a serotonin syndrome. These include tra- Because of the long half-life of fluoxetine and its active metabo-
madol [80] (which is metabolised by cytochrome P450 lite, norfluoxetine, this drug is essentially self-tapering, and
[CYP]2D6, an enzyme inhibited by fluoxetine), sumatriptan abrupt discontinuation is generally well-tolerated [97]. The inci-
[81] (presumably other triptans could interact in a similar dence of discontinuation symptoms tends to be lower than
manner) and meperidine [82]. with other antidepressants, including other SSRIs [98,99], with

Expert Opin. Drug Saf. (2004) 3(5) 499

Safety and side effect profile of fluoxetine

Table 2. Selected drug interactions reported for fluoxetine [103].

Drug Effects Consequences Reference

Of major importance, because these drugs are metabolised by CYP2D6

-blockers Elevation of plasma concentrations Possible hypotension [202]
(S-metoprolol, propafenone, timlol) due to CYP2D6 inhibition
Older antipsychotics (haloperidol, Elevation of plasma concentrations Extrapyramidal symptoms, [92]
fluphenazine, perphenazine) due to CYP2D6 inhibition impaired psychomotor
performance
TCAs Elevation of plasma concentrations Tricyclic toxicity [37,92,93]
due to CYP2D6 inhibition
Antiarrhythmic drugs (encainide, flecainide, Elevation of plasma concentrations Prolongation of the QT [94]
propafenone) due to CYP2D6 inhibition interval (cardiac repolarisation)
Minor pathways, but interactions reported
Carbamazepine Possible elevated concentrations Carbamazepine toxicity [92]
due to CYP2A4 inhibition
Phenytoin Elevation of plasma concentrations Phenytoin toxicity [92]
due to CYP2C9 inhibition
Atypical antipsychotics (clozapine) Elevation of plasma concentrations Potentially toxic [95]
due to CYP2C9 inhibition concentrations
Amphetamine Elevation of plasma concentrations Amphetamine toxicity [96]
due to CYP2C9 inhibition
Amiodarone Elevation of plasma concentrations Prolongation of the QT [37]
due to CYP2C9 inhibition interval (cardiac repolarisation)
CYP: Cytochrome P450; TCA: Tricyclic antidepressant.

headache being the only adverse event reported significantly generally safe and well-tolerated, including in younger and
more often than with placebo [100], although dizziness, light- older patients, pregnant women and those with concomi-
headedness and eye twitching have also been reported [101]. tant illnesses. Common adverse events reported with the
The long half-life of fluoxetine and norfluoxetine may be recommended dose of 20 mg/day are referable to the GI
an advantage in that withdrawal symptoms are expected to be system (nausea, diarrhoea and anorexia), and the nervous
uncommon, but could be of concern when starting other system (insomnia, somnolence, anxiety and asthenia). The
drugs. As noted above, it is recommended that 5 weeks elapse approved dose range is up to 80 mg/day, and when higher
before MAOIs are started. For drugs that are not serotonergic, doses are used, adverse events are more common. The long
for instance reboxetine, which is purely noradrenergic, a half-life of fluoxetine and its active metabolite essentially
switch without tapering of fluoxetine appears to be safe [102]. preclude a withdrawal phenomenon, and the drug can be
Dizziness, unstable gait, nausea, malaise and anxiety have considered to be self-tapering. It is an inhibitor of
been reported in a patient also taking clozapine [103]. CYP2D6 and other CYP enzymes, which increases the
Withdrawal symptoms are also important when patients chances for drug interactions.
intentionally or accidentally interrupt therapy. Five-day inter- The issue of suicidality associated with SSRIs is undergoing
ruption of fluoxetine treatment was found not to be associ- further evaluation. Overall, the risk/benefit ratio of fluoxetine
ated with the emergence of adverse events [104]. is very favourable.

4. Expert opinion and conclusion Disclosure

Fluoxetine is an SSRI that has been available for > 15 years, Joachim F Wernicke is an employee of Eli Lilly and Company,
and has been used to treat millions of patients with the manufacturer of Prozac, and participated in the develop-
depression and other neuropsychiatric disorders. It is ment of fluoxetine.

500 Expert Opin. Drug Saf. (2004) 3(5)

 Wernicke

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Websites
201. http://www.acnp.org/exec_summary.pdf
Preliminary report of the task force
on SSRIs and suicidal behaviour in
youth (2004).
202. http://medicine.iupui.edu/flockhart/
Drug interactions.
Excellent website for current information
on drug interactions of all types.

Affiliation
Joachim F Wernicke PhD MD
Lilly Corporate Center, Indianapolis,
IN 46285, USA
Tel: +1 317 433 5793; Fax: +1 317 655 9063;
E-mail: jfwernicke@lilly.com

504 Expert Opin. Drug Saf. (2004) 3(5)