WARNINGS
Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION – Discontinuation of Treatment with Fluoxetine , for a description of the risks of discontinuation of fluoxetine).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for fluoxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.
Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that fluoxetine is not approved for use in treating bipolar depression.
Rash and Possibly Allergic Events In U.S.
fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria.
Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash.
Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation.
Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these 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, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme.
Other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of fluoxetine, systemic 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, fluoxetine should be discontinued.
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SSRIs and SNRIs alone, including Fluoxetine Tablets USP treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including (MAOIs), or with antipsychotics or other dopamine antagonists.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.
Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Fluoxetine Tablets USP with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of Fluoxetine Tablets USP with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of Fluoxetine Tablets USP with serotonin precursors (such as tryptophan) is not recommended.
Treatment with Fluoxetine Tablets USP and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Potential Interaction with Thioridazine In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators.
The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity.
Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS ).
Thioridazine administration produces a dose-related prolongation of the QT c interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death.
This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS ).
DRUG INTERACTIONS
Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY ).
Drugs metabolized by CYP2D6 Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer.
Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution.
Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks.
Thus, his/her dosing requirements resemble those of poor metabolizers.
If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered.
Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs).
Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS ).
Drugs metabolized by CYP3A4 In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.
In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.
These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
CNS active drugs The risk of using fluoxetine in combination with other CNS active drugs has not been systematically evaluated.
Nonetheless, caution is advised if the concomitant administration of fluoxetine and such drugs is required.
In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY ).
Anticonvulsants Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.
Antipsychotics Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics.
Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine.
Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT c prolongation.
While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT c prolongation warrants restricting the concurrent use of pimozide and fluoxetine.
Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS ).
For thioridazine, see CONTRAINDICATIONS and WARNINGS .
Benzodiazepines The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY ).
Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.
Lithium There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine.
Cases of lithium toxicity and increased serotonergic effects have been reported.
Lithium levels should be monitored when these drugs are administered concomitantly.
Tryptophan Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.
Monoamine oxidase inhibitors See CONTRAINDICATIONS .
Other drugs effective in the treatment of major depressive disorder In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination.
This influence may persist for 3 weeks or longer after fluoxetine is discontinued.
Thus, the dose of 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 Accumulation and slow elimination under CLINICAL PHARMACOLOGY , and Drugs Metabolized by CYP2D6 under Drug Interactions).
Serotonergic drugs Based on the mechanism of action of SSRIs and SNRIs, including fluoxetine, and the potential for serotonin syndrome, caution is advised when fluoxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.
John’s Wort (see Serotonin Syndrome under WARNINGS ).
The concomitant use of fluoxetine with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan ).
Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.
If concomitant treatment of fluoxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Serotonin Syndrome under WARNINGS ).
Potential effects of coadministration of drugs tightly bound to plasma proteins Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs (see Accumulation and slow elimination under CLINICAL PHARMACOLOGY ).
Drugs that interfere with hemostasis (e.g., NSAIDs, aspirin, warfarin) Serotonin release by platelets plays an important role in hemostasis.
Epidemiological studies of the case- control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated 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.
Electroconvulsive therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine.
There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.
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, one patient experienced renal failure, and 22 patients had an unknown outcome.
One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome.
He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine.
Mixed-drug ingestion or other methods of suicide complicated all six overdoses in children that resulted in fatalities.
The largest ingestion in pediatric patients was 3 grams which was nonlethal.
Other important adverse 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.
Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose.
However, animal experiments can provide useful insights into possible treatment strategies.
The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively.
Acute high oral doses produced hyperirritability and convulsions in several animal species.
Among six dogs purposely overdosed with oral fluoxetine, five experienced grand mal seizures.
Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam.
In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically.
In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals.
Tachycardia and an increase in blood pressure were observed.
Consequently, the value of the ECG in predicting cardiac toxicity is unknown.
Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose ).
Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder.
Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended.
Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered.
Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for fluoxetine are known.
A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA.
In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other drugs effective in the treatment of major depressive disorder under 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 centres are listed in the Physicians’ Desk Reference (PDR) .
DESCRIPTION
Fluoxetine hydrochloride 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- p -tolyl)oxy]propylamine hydrochloride and has the molecular formula of C 17 H 18 F 3 NO•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 tablet contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol) or 20 mg (64.7 µmol) of fluoxetine.
In addition, each tablet also contains the following inactive ingredients: crospovidone, hypromellose, magnesium stearate, maize (corn) starch, microcrystalline cellulose, polyethylene glycol, silica colloidal anhydrous, and titanium dioxide.
Fluoxetine Hydrochloride Structural Formula
CLINICAL STUDIES
CLINICAL TRIALS Major Depressive Disorder Daily Dosing Adult The efficacy of fluoxetine for the treatment of patients with major depressive disorder (≥ 18 years of age) has been studied in 5- and 6- week placebo-controlled trials.
Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D).
Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor.
Two 6-week controlled studies (N=671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥ 60 years of age) with major depressive disorder.
In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤ 8.
Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse events did not differ between fluoxetine (12%) and placebo (9%).
A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤ 7 during each of the last 3 weeks of open-label treatment and absence of major depressive disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on fluoxetine 20 mg/day.
These patients (N=298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo.
At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of major depressive disorder for 2 weeks or a modified HAMD-17 score of ≥ 14 for 3 weeks) was observed for patients taking fluoxetine compared to those on placebo.
Pediatric (children and adolescents) The efficacy of fluoxetine 20 mg/day for the treatment of major depressive disorder in pediatric outpatients (N=315 randomized; 170 children ages 8 to < 13, 145 adolescents ages 13 to ≤ 18) has been studied in two 8- to 9-week placebo-controlled clinical trials.
In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo.
Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender.
Obsessive Compulsive Disorder Adult The effectiveness of fluoxetine for the treatment of obsessive-compulsive disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed fluoxetine doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo.
Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26.
In Study 1, patients receiving fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients.
In Study 2, patients receiving fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients.
While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the two higher dose groups.
The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Fluoxetine Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
Pediatric (children and adolescents) In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to < 13, 28 adolescents ages 13 to < 18) with OCD, patients received fluoxetine 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks.
The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability.
Fluoxetine produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS).
Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender.
Bulimia Nervosa The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia.
Patients in the 8-week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning.
Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo.
Patients in these three studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively.
In these three studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week.
The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study.
The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale.
In each of these three studies, the treatment effect, as measured by differences between fluoxetine 60 mg, and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from one to two episodes per week for binge-eating and two to four episodes per week for vomiting.
The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies.
Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging.
In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse.
Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline.
Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed.
Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.
Panic Disorder The effectiveness of fluoxetine in the treatment of panic disorder was demonstrated in two double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia.
Study 1 (N=180 randomized) was a 12-week flexible-dose study.
Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability.
A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.
Study 2 (N=214 randomized) was a 12-week flexible-dose study.
Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability.
A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.
HOW SUPPLIED
Fluoxetine Tablets USP are available as follows: 10 mg † , oval, normal convex, film coated, scored white tablet, debossed “FL 10” on one side and “G” on the other Bottles of 14 NDC 35356-0649-14 Bottles of 30 NDC 35356-0649-30 Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as described in the USP.
Protect from light.
Sarafem® is a trademark of Eli Lilly.
GERIATRIC USE
Geriatric Use U.S.
fluoxetine clinical trials included 687 patients ≥ 65 years of age and 93 patients ≥ 75 years of age.
The efficacy in geriatric patients has been established (see CLINICAL TRIALS ).
For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY .
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
SSRIs and SNRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia ).
INDICATIONS AND USAGE
Major Depressive Disorder Fluoxetine is indicated for the treatment of major depressive disorder.
Adult The efficacy of fluoxetine was established in 5- and 6-week trials with depressed adult and geriatric outpatients (≥ 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see CLINICAL TRIALS ).
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 five of the following nine 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 fluoxetine in hospitalized depressed patients have not been adequately studied.
The efficacy of fluoxetine 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.
Pediatric (children and adolescents) The efficacy of fluoxetine in children and adolescents was established in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see CLINICAL TRIALS ).
The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should be reevaluated periodically.
Obsessive Compulsive Disorder Adult Fluoxetine is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
The efficacy of fluoxetine was established in 13-week trials with obsessive-compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-R category of OCD (see CLINICAL TRIALS ).
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 fluoxetine in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials.
Therefore, the physician who elects to use fluoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).
Pediatric (children and adolescents) The efficacy of fluoxetine in children and adolescents was established in a 13-week, dose titration, clinical trial in patients with OCD, as defined in DSM-IV (see CLINICAL TRIALS ).
Bulimia Nervosa Fluoxetine is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa.
The efficacy of fluoxetine was established in 8-to 16-week trials for adult outpatients with moderate to severe bulimia nervosa, i.e., at least three bulimic episodes per week for 6 months (see CLINICAL TRIALS ).
The efficacy of fluoxetine 60 mg/day in maintaining a response, in patients with bulimia who responded during an 8-week acute treatment phase while taking fluoxetine 60 mg/day and were then observed for relapse during a period of up to 52 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS ).
Nevertheless, the physician who elects to use fluoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).
Panic Disorder Fluoxetine 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 fluoxetine was established in two 12-week clinical trials in patients whose diagnoses corresponded to the DSM-IV category of panic disorder (see CLINICAL TRIALS ).
Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four 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 fluoxetine in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials.
Therefore, the physician who elects to use fluoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).
PEDIATRIC USE
Pediatric Use The efficacy of fluoxetine for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤ 18 (see CLINICAL TRIALS ).
The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18 (see CLINICAL TRIALS ).
The safety and effectiveness in pediatric patients < 8 years of age in major depressive disorder and < 7 years of age in OCD have not been established.
Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤ 18) with major depressive disorder of OCD (see Pharmacokinetics under CLINICAL PHARMACOLOGY ).
The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine.
The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine (see ADVERSE REACTIONS ).
Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine treated patients and in 0 out of 190 (0%) placebo-treated patients.
Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined.
Consequently, regular monitoring for the occurrence of mania/hypomania is recommended.
As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients.
After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo.
In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels.
The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration.
In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients.
Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine (See WARNINGS, Clinical Worsening and Suicide Risk ).
Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine.
Some of these effects occurred at clinically relevant exposures.
In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose.
At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose.
When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible.
The reversibility of fluoxetine-induced muscle damage was not assessed.
Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals.
Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day.
Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3-0.8, 1-8, and 3-20 times, respectively, pediatric exposure at the MRD.
A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period.
When mice treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density.
These doses did not affect overall growth (body weight gain or femoral length).
The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m 2 ) basis.
In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age).
The dose used in this study is approximately equal to the pediatric MRD on a mg/m 2 basis.
Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.
Fluoxetine is approved for use in pediatric patients with MDD and OCD (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk ).
Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need.
PREGNANCY
Pregnancy Pregnancy Category C In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m 2 basis) throughout organogenesis.
However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) during gestation and lactation.
There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation.
The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m 2 basis).
Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects Neonates exposed to fluoxetine 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 (see Monoamine oxidase inhibitors under 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 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality.
In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy.
There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk.
The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION ).
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.
NUSRING MOTHERS
Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.
In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL.
The concentration in the mother’s plasma was 295 ng/mL.
No adverse effects on the infant were reported.
In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools.
The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.
BOXED WARNING
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of fluoxetine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised of the need for close observation and communication with the prescriber.
Fluoxetine is approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD).
(See WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use .)
INFORMATION FOR PATIENTS
Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine and should counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for fluoxetine.
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 fluoxetine.
Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and triptans, tramadol or other serotonergic agents.
Because fluoxetine may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.
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 Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding ( see PRECAUTIONS, General, Abnormal Bleeding ).
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.
DOSAGE AND ADMINISTRATION
Major Depressive Disorder Initial Treatment Adult In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day.
Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases.
Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.
A dose increase may be considered after several weeks if insufficient clinical improvement is observed.
Doses above 20 mg/day may be administered on a once-a-day (morning) or B.I.D.
schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day.
Pediatric (children and adolescents) In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of major depressive disorder, patients were administered fluoxetine doses of 10 to 20 mg/day (see CLINICAL TRIALS ).
Treatment should be initiated with a dose of 10 or 20 mg/day.
After 1 week at 10 mg/day, the dose should be increased to 20 mg/day.
However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day.
A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed.
All patients As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer.
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 (see Geriatric Use under PRECAUTIONS ), and for patients with concurrent disease or on multiple concomitant medications.
Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY , and Use in Patients with Concomitant Illness under PRECAUTIONS ).
Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy.
Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Daily Dosing Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in major depressive disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day (see CLINICAL TRIALS ).
Switching Patients to a Tricyclic Antidepressant (TCA) Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see Other drugs effective in the treatment of major depressive disorder under PRECAUTIONS, Drug Interactions ).
Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with fluoxetine.
In addition, at least 5 weeks, perhaps longer, should be allowed after stopping fluoxetine before starting an MAOI (see CONTRAINDICATIONS and PRECAUTIONS ).
Obsessive Compulsive Disorder Initial Treatment Adult In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo (see CLINICAL TRIALS ).
In one of these studies, no dose-response relationship for effectiveness was demonstrated.
Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.
Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed.
The full therapeutic effect may be delayed until 5 weeks of treatment or longer.
Doses above 20 mg/day may be administered on a once-a-day (i.e., morning) or B.I.D.
schedule (i.e., morning and noon).
A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD.
The maximum fluoxetine dose should not exceed 80 mg/day.
Pediatric (children and adolescents) In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS ).
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 As with the use of fluoxetine in the treatment of major depressive disorder, 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 (see Geriatric Use under PRECAUTIONS ), and for patients with concurrent disease or on multiple concomitant medications.
Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY , and Use in Patients with Concomitant Illness under PRECAUTIONS ).
Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient.
Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit.
However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.
Bulimia Nervosa Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo (see CLINICAL TRIALS ).
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 fluoxetine 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 (see Geriatric Use under PRECAUTIONS ), and for patients with concurrent disease or on multiple concomitant medications.
Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY , and Use in Patients with Concomitant Illness under PRECAUTIONS ).
Maintenance/Continuation Treatment Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment (see CLINICAL TRIALS ).
Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
Panic Disorder Initial Treatment In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of panic disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day (see CLINICAL TRIALS ).
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 two flexible-dose clinical trials was 20 mg/day.
A dose increase may be considered after several weeks if no clinical improvement is observed.
Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with panic disorder.
As with the use of fluoxetine 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 (see Geriatric Use under PRECAUTIONS ), and for patients with concurrent disease or on multiple concomitant medications.
Dosage adjustments for renal impairment are not routinely necessary (see Liver disease and Renal disease under CLINICAL PHARMACOLOGY , and Use in Patients with Concomitant Illness under PRECAUTIONS ).
Maintenance/Continuation Treatment While there are no systematic studies that answer the question of how long to continue fluoxetine, 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.
Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to fluoxetine and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS ).
When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
The physician may consider tapering fluoxetine in the third trimester.
Discontinuation of Treatment with Fluoxetine Symptoms associated with discontinuation of fluoxetine and other SSRIs and SNRIs, have been reported (see PRECAUTIONS ).
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.