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Prozac
Overview
What is Prozac?
Prozac (fluoxetine capsules, USP and
fluoxetine oral solution, USP) is a psychotropic drug for oral administration.
It is also marketed for the treatment of premenstrual dysphoric disorder
(Sarafem, fluoxetine hydrochloride). It is designated
(±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro--tolyl)oxy]propylamine hydrochloride and has the empirical
formula of CHFNO•HCl. Its molecular weight is 345.79. The structural formula
is:
Fluoxetine hydrochloride is a white to off–white crystalline solid with a
solubility of 14 mg/mL in water.
Each Pulvule contains fluoxetine hydrochloride
equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of
fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium
dioxide, iron oxide, and other inactive ingredients. The 10– and 20–mg Pulvules
also contain FDandC Blue No. 1, and the 40–mg Pulvule also contains FDnadC
Blue No. 1 and FDandC Yellow No. 6.
The oral solution contains fluoxetine hydrochloride equivalent to
20 mg/5 mL (64.7 μmol) of fluoxetine. It also contains alcohol 0.23%, benzoic
acid, flavoring agent, glycerin, purified water, and sucrose.
Prozac Weekly™ capsules, a delayed–release formulation, contain
enteric–coated pellets of fluoxetine hydrochloride equivalent to 90 mg
(291 μmol) of fluoxetine. The capsules also contain DandC Yellow No. 10,
FDandC Blue No. 2, gelatin, hypromellose, hypromellose acetate succinate,
sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl
citrate, and other inactive ingredients.
What does Prozac look like?
What are the available doses of Prozac?
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How should I use Prozac?
Prozac is indicated for the treatment of major depressive
disorder.
Adult
see
A major depressive episode (DSM–IV) implies a prominent and relatively
persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood
that usually interferes with daily functioning, and includes at least 5 of the
following 9 symptoms: depressed mood, loss of interest in usual activities,
significant change in weight and/or appetite, insomnia or hypersomnia,
psychomotor agitation or retardation, increased fatigue, feelings of guilt or
worthlessness, slowed thinking or impaired concentration, a suicide attempt or
suicidal ideation.
The effects of Prozac in hospitalized depressed patients have not been
adequately studied.
The efficacy of Prozac 20 mg once daily in maintaining a response in major
depressive disorder for up to 38 weeks following 12 weeks of open–label acute
treatment (50 weeks total) was demonstrated in a placebo–controlled trial.
The efficacy of Prozac Weekly once weekly in maintaining a response in major
depressive disorder has been demonstrated in a placebo–controlled trial for up
to 25 weeks following open–label acute treatment of 13 weeks with Prozac 20 mg
daily for a total treatment of 38 weeks. However, it is unknown whether or not
Prozac Weekly given on a once–weekly basis provides the same level of protection
from relapse as that provided by Prozac 20 mg daily ( ).
Pediatric (children and adolescents)
see
The usefulness of the drug in adult and pediatric patients receiving
fluoxetine for extended periods should be reevaluated periodically.
Adult
The efficacy of Prozac was established in 13–week trials with obsessive
compulsive outpatients whose diagnoses corresponded most closely to the
DSM–III–R category of OCD (
).
OCD is characterized by recurrent and persistent ideas, thoughts, impulses,
or images (obsessions) that are ego–dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as
excessive or unreasonable.
The effectiveness of Prozac in long–term use, i.e., for more than 13 weeks,
has not been systematically evaluated in placebo–controlled trials. Therefore,
the physician who elects to use Prozac for extended periods should periodically
reevaluate the long–term usefulness of the drug for the individual patient
(
).
Pediatric (children and adolescents)
see
Prozac is indicated for the treatment of binge–eating and
vomiting behaviors in patients with moderate to severe bulimia nervosa.
The efficacy of Prozac was established in 8– to 16–week trials for adult
outpatients with moderate to severe bulimia nervosa, i.e., at least 3 bulimic
episodes per week for 6 months (
).
The efficacy of Prozac 60 mg/day in maintaining a response, in patients with
bulimia who responded during an 8–week acute treatment phase while taking Prozac
60 mg/day and were then observed for relapse during a period of up to 52 weeks,
was demonstrated in a placebo–controlled trial (
). Nevertheless, the physician who elects
to use Prozac for extended periods should periodically reevaluate the long–term
usefulness of the drug for the individual patient (
).
Prozac is indicated for the treatment of panic disorder, with or
without agoraphobia, as defined in DSM–IV. Panic disorder is characterized by
the occurrence of unexpected panic attacks, and associated concern about having
additional attacks, worry about the implications or consequences of the attacks,
and/or a significant change in behavior related to the attacks.
The efficacy of Prozac was established in two 12–week clinical trials in
patients whose diagnoses corresponded to the DSM–IV category of panic disorder
(
).
Panic disorder (DSM–IV) is characterized by recurrent, unexpected panic
attacks, i.e., a discrete period of intense fear or discomfort in which 4 or
more of the following symptoms develop abruptly and reach a peak within 10
minutes: 1) palpitations, pounding heart, or accelerated heart rate;
2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or
smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or
abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) fear
of losing control; 10) fear of dying; 11) paresthesias (numbness or tingling
sensations); 12) chills or hot flashes.
The effectiveness of Prozac in long–term use, i.e., for more than 12 weeks,
has not been established in placebo–controlled trials. Therefore, the physician
who elects to use Prozac for extended periods should periodically reevaluate the
long–term usefulness of the drug for the individual patient (
).
Adult
A dose increase may be considered after several weeks if insufficient
clinical improvement is observed. Doses above 20 mg/day may be administered on a
once–a–day (morning) or BID schedule (i.e., morning and noon) and should not
exceed a maximum dose of 80 mg/day.
Pediatric (children and adolescents)
see
However, due to higher plasma levels in lower weight children, the starting
and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may
be considered after several weeks if insufficient clinical improvement is
observed.
All patients
As with many other medications, a lower or less frequent dosage should be
used in patients with hepatic impairment. A lower or less frequent dosage should
also be considered for the elderly (
PRECAUTIONS), and for patients with concurrent disease or on multiple
concomitant medications. Dosage adjustments for renal impairment are not
routinely necessary (
CLINICAL PHARMACOLOGY,
PRECAUTIONS).
It is generally agreed that acute episodes of major depressive
disorder require several months or longer of sustained pharmacologic therapy.
Whether the dose needed to induce remission is identical to the dose needed to
maintain and/or sustain euthymia is unknown.
Systematic evaluation of Prozac in adult patients has shown that
its efficacy in major depressive disorder is maintained for periods of up to 38
weeks following 12 weeks of open–label acute treatment (50 weeks total) at a
dose of 20 mg/day (
).
Systematic evaluation of Prozac Weekly in adult patients has
shown that its efficacy in major depressive disorder is maintained for periods
of up to 25 weeks with once–weekly dosing following 13 weeks of open–label
treatment with Prozac 20 mg once daily. However, therapeutic equivalence of
Prozac Weekly given on a once–weekly basis with Prozac 20 mg given daily for
delaying time to relapse has not been established (
).
Weekly dosing with Prozac Weekly capsules is recommended to be initiated 7
days after the last daily dose of Prozac 20 mg (
CLINICAL PHARMACOLOGY).
If satisfactory response is not maintained with Prozac Weekly, consider
reestablishing a daily dosing regimen (
).
Dosage of a TCA may need to be reduced, and plasma TCA
concentrations may need to be monitored temporarily when fluoxetine is
coadministered or has been recently discontinued (
PRECAUTIONS, Drug Interactions).
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 an MAOI (
).
Adult
see
Doses above 20 mg/day may be administered on a once–a–day (i.e., morning) or
BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is
recommended; however, doses of up to 80 mg/day have been well tolerated in open
studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day.
Pediatric (children and adolescents)
see
In adolescents and higher weight children, treatment should be initiated with
a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day.
Additional dose increases may be considered after several more weeks if
insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day
is recommended.
In lower weight children, treatment should be initiated with a dose of
10 mg/day. Additional dose increases may be considered after several more weeks
if insufficient clinical improvement is observed. A dose range of 20 to
30 mg/day is recommended. Experience with daily doses greater than 20 mg is very
minimal, and there is no experience with doses greater than 60 mg.
All patients
see
under
see
and
under
and
under
While there are no systematic studies that answer the question of
how long to continue Prozac, OCD is a chronic condition and it is reasonable to
consider continuation for a responding patient. Although the efficacy of Prozac
after 13 weeks has not been documented in controlled trials, adult patients have
been continued in therapy under double–blind conditions for up to an additional
6 months without loss of benefit. However, dosage adjustments should be made to
maintain the patient on the lowest effective dosage, and patients should be
periodically reassessed to determine the need for treatment.
In the controlled clinical trials of fluoxetine supporting its
effectiveness in the treatment of bulimia nervosa, patients were administered
fixed daily fluoxetine doses of 20 or 60 mg, or placebo (
). Only the
60–mg dose was statistically significantly superior to placebo in reducing the
frequency of binge–eating and vomiting. Consequently, the recommended dose is
60 mg/day, administered in the morning. For some patients it may be advisable to
titrate up to this target dose over several days. Fluoxetine doses above
60 mg/day have not been systematically studied in patients with bulimia.
As with the use of Prozac in the treatment of major depressive disorder and
OCD, a lower or less frequent dosage should be used in patients with hepatic
impairment. A lower or less frequent dosage should also be considered for the
elderly (
PRECAUTIONS), and for patients with
concurrent disease or on multiple concomitant medications. Dosage adjustments
for renal impairment are not routinely necessary (
CLINICAL PHARMACOLOGY,
PRECAUTIONS).
Systematic evaluation of continuing Prozac 60 mg/day for periods
of up to 52 weeks in patients with bulimia who have responded while taking
Prozac 60 mg/day during an 8–week acute treatment phase has demonstrated a
benefit of such maintenance treatment (
). Nevertheless, patients should be
periodically reassessed to determine the need for maintenance treatment.
In the controlled clinical trials of fluoxetine supporting its
effectiveness in the treatment of panic disorder, patients were administered
fluoxetine doses in the range of 10 to 60 mg/day (
). Treatment
should be initiated with a dose of 10 mg/day. After 1 week, the dose should be
increased to 20 mg/day. The most frequently administered dose in the 2
flexible–dose clinical trials was 20 mg/day.
A dose increase may be considered after several weeks if no clinical
improvement is observed. Fluoxetine doses above 60 mg/day have not been
systematically evaluated in patients with panic disorder.
As with the use of Prozac in other indications, a lower or less frequent
dosage should be used in patients with hepatic impairment. A lower or less
frequent dosage should also be considered for the elderly (
PRECAUTIONS), and for patients with concurrent
disease or on multiple concomitant medications. Dosage adjustments for renal
impairment are not routinely necessary (
CLINICAL PHARMACOLOGY,
PRECAUTIONS).
While there are no systematic studies that answer the question of
how long to continue Prozac, panic disorder is a chronic condition and it is
reasonable to consider continuation for a responding patient. Nevertheless,
patients should be periodically reassessed to determine the need for continued
treatment.
Neonates exposed to Prozac and other SSRIs or SNRIs, late in the
third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding (
). When treating
pregnant women with Prozac during the third trimester, the physician should
carefully consider the potential risks and benefits of treatment. The physician
may consider tapering Prozac in the third trimester.
Symptoms associated with discontinuation of Prozac and other
SSRIs and SNRIs, have been reported (
). Patients should be monitored for these
symptoms when discontinuing treatment. A gradual reduction in the dose rather
than abrupt cessation is recommended whenever possible. If intolerable symptoms
occur following a decrease in the dose or upon discontinuation of treatment,
then resuming the previously prescribed dose may be considered. Subsequently,
the physician may continue decreasing the dose but at a more gradual rate.
Plasma fluoxetine and norfluoxetine concentration decrease gradually at the
conclusion of therapy which may minimize the risk of discontinuation symptoms
with this drug.
What interacts with Prozac?
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What are the warnings of Prozac?
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What are the precautions of Prozac?
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What are the side effects of Prozac?
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What should I look out for while using Prozac?
Prozac is contraindicated in patients known to be hypersensitive
to it.
Monoamine oxidase inhibitors
see
under
Pimozide
see
Thioridazine
see
Clinical Worsening and Suicide Risk
The pooled analyses of placebo–controlled trials in children and adolescents
with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders
included a total of 24 short–term trials of 9 antidepressant drugs in over 4400
patients. The pooled analyses of placebo–controlled trials in adults with MDD or
other psychiatric disorders included a total of 295 short–term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There
were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences
(drug versus placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug–placebo difference in the
number of cases of suicidality per 1000 patients treated) are provided in Table
No suicides occurred in any of the pediatric trials. There were suicides in
the adult trials, but the number was not sufficient to reach any conclusion
about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer–term use, i.e.,
beyond several months. However, there is substantial evidence from
placebo-controlled maintenance trials in adults with depression that the use of
antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any
indication should be monitored appropriately and observed closely for clinical
worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania, have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric. Although a
causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established,
there is concern that such symptoms may represent precursors to emerging
suicidality.
Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is
persistently worse, or who are experiencing emergent suicidality or symptoms
that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient’s
presenting symptoms.
If the decision has been made to discontinue treatment, medication should be
tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can be associated with certain symptoms (
, for a description of the risks of
discontinuation of Prozac).
Families and caregivers of patients being treated with
antidepressants for major depressive disorder or other indications, both
psychiatric and nonpsychiatric, should be alerted about the need to monitor
patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to health care providers.
Such monitoring should include daily observation by families and
caregivers.
It should be noted that Prozac is approved in the pediatric population only
for major depressive disorder and obsessive compulsive disorder.
Screening Patients for Bipolar Disorder
Rash and Possibly Allergic Events
In premarketing clinical trials, 2 patients are known to have developed a
serious cutaneous systemic illness. In neither patient was there an unequivocal
diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the
other, a severe desquamating syndrome that was considered variously to be a
vasculitis or erythema multiforme. Other patients have had systemic syndromes
suggestive of serum sickness.
Since the introduction of Prozac, 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.
Serotonin Syndrome
The concomitant use of Prozac with MAOIs intended to treat depression is
contraindicated (
PRECAUTIONS).
If concomitant treatment Prozac with a 5–hydroxytryptamine receptor agonist
(triptan) is clinically warranted, careful observation of the patient is
advised, particularly during treatment initiation and dose increases (
PRECAUTIONS).
The concomitant use of Prozac with serotonin precursors (such as tryptophan)
is not recommended (
PRECAUTIONS).
Potential Interaction with Thioridazine
see
Thioridazine administration produces a dose–related prolongation of the
QT 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 (
).
What might happen if I take too much Prozac?
Worldwide exposure to fluoxetine hydrochloride is estimated to be
over 38 million patients (circa 1999). Of the 1578 cases of overdose involving
fluoxetine hydrochloride, alone or with other drugs, reported from this
population, there were 195 deaths.
Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34
resulted in a fatal outcome, 378 completely recovered, and 15 patients
experienced sequelae after overdosage, including abnormal accommodation,
abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction,
vertigo, tremor, elevated blood pressure, impotence, movement disorder, and
hypomania. The remaining 206 patients had an unknown outcome. The most common
signs and symptoms associated with non–fatal overdosage were seizures,
somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of
fluoxetine hydrochloride in adult patients was 8 grams in a patient who took
fluoxetine alone and who subsequently recovered. However, in an adult patient
who took fluoxetine alone, an ingestion as low as 520 mg has been associated
with lethal outcome, but causality has not been established.
Among pediatric patients (ages 3 months to 17 years), there were 156 cases of
overdose involving fluoxetine alone or in combination with other drugs. Six
patients died, 127 patients completely recovered, 1 patient experienced renal
failure, and 22 patients had an unknown outcome. One of the six fatalities was a
9–year–old boy who had a history of OCD, Tourette’s syndrome with tics,
attention deficit disorder, and fetal alcohol syndrome. He had been receiving
100 mg of fluoxetine daily for 6 months in addition to clonidine,
methylphenidate, and promethazine. Mixed–drug ingestion or other methods of
suicide complicated all 6 overdoses in children that resulted in fatalities. The
largest ingestion in pediatric patients was 3 grams which was nonlethal.
Other important adverse events reported with fluoxetine overdose (single or
multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval
prolongation and ventricular tachycardia, including torsades de pointes–type
arrhythmias), hypotension, mania, neuroleptic malignant syndrome–like events,
pyrexia, stupor, and syncope.
Studies in animals do not provide precise or necessarily valid
information about the treatment of human overdose. However, animal experiments
can provide useful insights into possible treatment strategies.
The oral median lethal dose in rats and mice was found to be 452 and
248 mg/kg, respectively. Acute high oral doses produced hyperirritability and
convulsions in several animal species.
Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand
mal seizures. Seizures stopped immediately upon the bolus intravenous
administration of a standard veterinary dose of diazepam. In this short–term
study, the lowest plasma concentration at which a seizure occurred was only
twice the maximum plasma concentration seen in humans taking 80 mg/day,
chronically.
In a separate single–dose study, the ECG of dogs given high doses did not
reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase
in blood pressure were observed. Consequently, the value of the ECG in
predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily
be monitored in cases of human overdose (
).
Treatment should consist of those general measures employed in
the management of overdosage with any drug effective in the treatment of major
depressive disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac
rhythm and vital signs. General supportive and symptomatic measures are also
recommended. Induction of emesis is not recommended. Gastric lavage with a
large–bore orogastric tube with appropriate airway protection, if needed, may be
indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of
distribution of this drug, forced diuresis, dialysis, hemoperfusion, and
exchange transfusion are unlikely to be of benefit. No specific antidotes for
fluoxetine are known.
A specific caution involves patients who are taking or have recently taken
fluoxetine and might ingest excessive quantities of a TCA. In such a case,
accumulation of the parent tricyclic and/or an active metabolite may increase
the possibility of clinically significant sequelae and extend the time needed
for close medical observation (
PRECAUTIONS).
Based on experience in animals, which may not be relevant to humans,
fluoxetine–induced seizures that fail to remit spontaneously may respond to
diazepam.
In managing overdosage, consider the possibility of multiple drug
involvement. The physician should consider contacting a poison control center
for additional information on the treatment of any overdose. Telephone numbers
for certified poison control centers are listed in the .
How should I store and handle Prozac?
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Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The antidepressant, antiobsessive compulsive, and antibulimic
actions of fluoxetine are presumed to be linked to its inhibition of CNS
neuronal uptake of serotonin. Studies at clinically relevant doses in man have
demonstrated that fluoxetine blocks the uptake of serotonin into human
platelets. Studies in animals also suggest that fluoxetine is a much more potent
uptake inhibitor of serotonin than of norepinephrine.
Antagonism of muscarinic, histaminergic, and α–adrenergic receptors has been hypothesized to be associated
with various anticholinergic, sedative, and cardiovascular effects of classical
tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other
membrane receptors from brain tissue much less potently in vitro than do the
tricyclic drugs.
Systemic bioavailability
The Pulvule, oral solution, and Prozac Weekly capsule dosage forms of
fluoxetine are bioequivalent. Food does not appear to affect the systemic
bioavailability of fluoxetine, although it may delay its absorption by 1 to 2
hours, which is probably not clinically significant. Thus, fluoxetine may be
administered with or without food. Prozac Weekly capsules, a delayed–release
formulation, contain enteric–coated pellets that resist dissolution until
reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The
enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours
relative to the immediate–release formulations.
Protein binding
see
Enantiomers
R
S
S
Metabolism
S
R
S
R
Clinical issues related to
metabolism/elimination
Variability in metabolism
S
S
S
R
Because fluoxetine’s metabolism, like that of a number of other compounds
including TCAs and other selective serotonin reuptake inhibitors (SSRIs),
involves the CYP2D6 system, concomitant therapy with drugs also metabolized by
this enzyme system (such as the TCAs) may lead to drug interactions (
PRECAUTIONS).
Accumulation and slow elimination
The long elimination half–lives of fluoxetine and norfluoxetine assure that,
even when dosing is stopped, active drug substance will persist in the body for
weeks (primarily depending on individual patient characteristics, previous
dosing regimen, and length of previous therapy at discontinuation). This is of
potential consequence when drug discontinuation is required or when drugs are
prescribed that might interact with fluoxetine and norfluoxetine following the
discontinuation of Prozac.
Weekly dosing
C for fluoxetine following the 90–mg dose was
approximately 1.7–fold higher than the C value for the
established 20–mg once–daily regimen following transition the next day to the
once–weekly regimen. In contrast, when the first 90–mg once–weekly dose and the
last 20–mg once–daily dose were separated by 1 week, C
values were similar. Also, there was a transient increase in the average
steady–state concentrations of fluoxetine observed following transition the next
day to the once–weekly regimen. From a pharmacokinetic perspective, it may be
better to separate the first 90–mg weekly dose and the last 20–mg once–daily
dose by 1 week (
).
Liver disease
see
and
Renal disease
see
under
and
Geriatric pharmacokinetics
Non-Clinical Toxicology
Prozac is contraindicated in patients known to be hypersensitive to it.Monoamine oxidase inhibitors
see
under
Pimozide
see
Thioridazine
see
Clinical Worsening and Suicide Risk
The pooled analyses of placebo–controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short–term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo–controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short–term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug–placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer–term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms ( , for a description of the risks of discontinuation of Prozac).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.
It should be noted that Prozac is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder.
Screening Patients for Bipolar Disorder
Rash and Possibly Allergic Events
In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of Prozac, 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.
Serotonin Syndrome
The concomitant use of Prozac with MAOIs intended to treat depression is contraindicated ( PRECAUTIONS).
If concomitant treatment Prozac with a 5–hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases ( PRECAUTIONS).
The concomitant use of Prozac with serotonin precursors (such as tryptophan) is not recommended ( PRECAUTIONS).
Potential Interaction with Thioridazine
see
Thioridazine administration produces a dose–related prolongation of the QT 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 ( ).
Abnormal Bleeding
Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation ( ).
Anxiety and Insomnia
In US placebo–controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Prozac and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Prozac and in 7% of patients treated with placebo.
In US placebo–controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with Prozac 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Prozac 60 mg and in 9% and 5% of patients treated with placebo.
Among the most common adverse events associated with discontinuation (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 US placebo–controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) ( ).
Altered Appetite and Weight
In US placebo–controlled clinical trials for major depressive disorder, 11% of patients treated with Prozac and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Prozac because of anorexia or weight loss ( PRECAUTIONS).
In US placebo–controlled clinical trials for OCD, 17% of patients treated with Prozac and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia ( PRECAUTIONS).
In US placebo–controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16–week double–blind trial. Weight change should be monitored during therapy.
Activation of Mania/Hypomania
see also
under
In US placebo–controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Prozac and no patients treated with placebo. No patients reported mania/hypomania in US placebo–controlled clinical trials for bulimia. In all US Prozac clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania ( PRECAUTIONS).
Hyponatremia
see
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
Seizures
The Long Elimination Half–Lives of Fluoxetine and its Metabolites
see
and
Use in Patients with Concomitant Illness
Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Prozac in double–blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.
In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half–lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis.
Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma ( CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary ( ).
In patients with diabetes, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, 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 Prozac is instituted or discontinued.
Interference with Cognitive and Motor Performance
Discontinuation of Treatment with Prozac
see
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Prozac and should counsel them in its appropriate use. A patient Medication Guide about“Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for Prozac. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Prozac.
Clinical Worsening and Suicide Risk
Serotonin Syndrome
Because Prozac may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.
Patients should be advised to inform their physician if they are taking or plan to take any prescription or over–the–counter drugs, or alcohol.
Abnormal Bleeding
see
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast–feeding an infant.
Patients should be advised to notify their physician if they develop a rash or hives.
There are no specific laboratory tests recommended.
As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility ( CLINICAL PHARMACOLOGY).
Drugs metabolized by CYP2D6
see
and
Drugs metabolized by CYP3A4
CNS active drugs
see
under
Anticonvulsants
Antipsychotics
see
Benzodiazepines
see
under
Lithium
Tryptophan
Monoamine oxidase inhibitors
Other drugs effective in the treatment of major depressive disorder
see
under
and
under
Serotonergic drugs
see
under
see
Triptans
see
under
Potential effects of coadministration of drugs tightly bound to plasma proteins
see
under
Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin)
Electroconvulsive therapy (ECT)
There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m basis) was not observed.
Carcinogenicity
Mutagenicity
Impairment of fertility
see
In embryo–fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no–effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Neonates exposed to Prozac and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), 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 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome ( CONTRAINDICATIONS).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1–2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case–control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six–fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with Prozac during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment ( ). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
The effect of Prozac on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
Because Prozac is excreted in human milk, nursing while on Prozac is not recommended. In one breast–milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on Prozac developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.
The efficacy of Prozac for the treatment of major depressive disorder was demonstrated in two 8– to 9–week placebo–controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 ( ).
Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered Prozac in panic clinical trials. 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.
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 physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
Incidence in major depressive disorder, OCD, bulimia, and panic disorder placebo–controlled clinical trials (excluding data from extensions of trials)
Other adverse events in pediatric patients (children and adolescents)
The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo–controlled trials (N=418 randomized; 228 fluoxetine–treated; 190 placebo–treated) was mania/hypomania (1.8% for fluoxetine–treated, 0% for placebo–treated). In these clinical trials, only a primary event associated with discontinuation was collected.
Events observed in Prozac Weekly clinical trials
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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