Major Depressive Disorder
Fluoxetine is indicated for the treatment of Major Depressive Disorder (MDD) [see Clinical Studies (14.1)]. The efficacy of Fluoxetine in MDD was established in one 5 week trial, three 6 week trials, and one maintenance study in adults. The efficacy of Fluoxetine was also established in two 8 to 9 week trials in pediatric patients aged 8 to 18 years; doses greater than 20 mg/day have not been studied in pediatric patients with MDD.
The usefulness of the drug in adult and pediatric patients receiving Fluoxetine for extended periods should periodically be re-evaluated [see Dosage and Administration (2.1)].
Obsessive Compulsive Disorder
Fluoxetine is indicated for the treatment of Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)]. The efficacy of Fluoxetine in OCD was demonstrated in two 13 week trials in adults and one 13 week trial in pediatric patients aged 7 to 17 years.
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 re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)].
Bulimia Nervosa
Fluoxetine is indicated for the treatment of moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)]. The efficacy of Fluoxetine in Bulimia was demonstrated in two 8 week trials and one 16 week trial in adults.
The physician who elects to use Fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].
Panic Disorder
Fluoxetine is indicated for the treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4)]. The efficacy of Fluoxetine in Panic Disorder was demonstrated in two 12 week trials in adults.
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 re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)].
Fluoxetine Dosage and Administration
This product is only available in a 60 mg dosage form. A 30 mg dose may be achieved with one-half of the scored tablet. Use of this product requires initial titration with another Fluoxetine product according to the dosing guidelines indicated below.
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 MDD 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 daily (morning) or twice daily 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 MDD, patients were administered Fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. This product is only available in a 60 mg dosage form. Administration of doses with demonstrated efficacy of Fluoxetine 10 to 20 mg/day in pediatric MDD requires the use of another formulation.
All patients — As with other drugs effective in the treatment of MDD, the full effect may be delayed until 4 weeks of treatment or longer.
Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of MDD 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 MDD is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)].
Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when Fluoxetine is coadministered or has been recently discontinued [see Drug Interactions (7.8)].
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 (4) and Drug Interactions (7.1)].
Obsessive Compulsive Disorder
Initial Treatment
Adults — In the controlled clinical trials of Fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of Fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer.
Doses above 20 mg/day may be administered on a once daily (i.e., morning) or twice daily schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum Fluoxetine dose should not exceed 80 mg/day.
Pediatric (children and adolescents) — In the controlled clinical trial of Fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered Fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)].
In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended.
In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg.
Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue Fluoxetine, 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 Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia.
Maintenance/Continuation Treatment — Systematic evaluation of continuing Fluoxetine 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 Studies (14.3)]. 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 Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder.
Maintenance/Continuation Treatment — While there are no systematic studies that answer the question of how long to continue Fluoxetine, 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.
Dosing in Specific Populations
Treatment of Pregnant Women During the Third Trimester — When treating pregnant women with Fluoxetine during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. The physician may consider tapering Fluoxetine in the third trimester [see Use in Specific Populations (8.1)].
Geriatrics — A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)].
Hepatic Impairment — As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].
Dosage Forms and Strengths
Fluoxetine tablets, USP 60 mg, are available as 60 mg (Fluoxetine base equivalent), film coated, functionally scored, capsule-shaped, white tablets debossed with “FL 60” on one side (“FL” above the score and “60” below the score).
Contraindications
The use of Fluoxetine is contraindicated with the following:
- Monoamine Oxidase Inhibitors: Do not use with an MAOI or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping Fluoxetine before treatment with an MAOI [see Drug Interactions (7.1)]
- Pimozide: Do not use with pimozide due to risk of QTc prolongation [see Drug Interactions (7.8)].
- Thioridazine: Do not use with thioridazine due to QTc interval prolongation. Do not use thioridazine within 5 weeks of discontinuing Fluoxetine [see Drug Interactions (7.8)].
- Known hypersensitivity to Fluoxetine: Do not use this product in patients with known hypersensitivity to Fluoxetine due to risk of anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria [see Warnings and Precautions (5.3)].
Warnings and Precautions
Clinical Worsening and Suicide Risk
Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with 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, 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 1.
Table 1. Suicidality per 1000 Patients Treated
| 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 MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.13)].
Families and caregivers of patients being treated with antidepressants for MDD 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.
It should be noted that Fluoxetine is approved in the pediatric population only for MDD and OCD.
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions
The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Fluoxetine treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Fluoxetine with MAOIs intended to treat depression is contraindicated [see Contraindications (4) and Drug Interactions (7.1)].
If concomitant treatment of Fluoxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.4)].
The concomitant use of Fluoxetine with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.3)].
Treatment with Fluoxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur, and supportive symptomatic treatment should be initiated.
Allergic Reactions and Rash
In U.S. Fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of Fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.
In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of Fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.
Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.
Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.
Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Fluoxetine should be discontinued.
Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that Fluoxetine monotherapy is not approved for use in treating Bipolar I Disorder.
In U.S. placebo-controlled clinical trials for MDD, mania/hypomania was reported in 0.1% of patients treated with Fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of MDD [see Use in Specific Populations (8.4)].
In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In all U.S. Fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].
Seizures
In U.S. placebo-controlled clinical trials for MDD, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with Fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In all U.S. Fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of MDD. Fluoxetine should be introduced with care in patients with a history of seizures. There have been rare reports of prolonged seizures in patients on Fluoxetine receiving ECT treatment.
Altered Appetite and Weight
Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with Fluoxetine.
In U.S. placebo-controlled clinical trials for MDD, 11% of patients treated with Fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Fluoxetine because of anorexia or weight loss [see Use in Specific Populations (8.4)].
In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with Fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Fluoxetine because of anorexia [see Use in Specific Populations (8.4)].
In U.S. placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with Fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16 week double-blind trial. Weight change should be monitored during therapy.
Abnormal Bleeding
SNRIs and SSRIs, including Fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.6)].
Hyponatremia
Hyponatremia has been reported during treatment with SNRIs and SSRIs, including Fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of Fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
Anxiety and Insomnia
In U.S. placebo-controlled clinical trials for MDD, 12% to 16% of patients treated with Fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.
In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Fluoxetine and in 7% of patients treated with placebo.
In U.S. placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with Fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.
Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for Fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S. placebo-controlled Fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in MDD) [see Adverse Reactions (6.1)].
Use in Patients with Concomitant Illness
Clinical experience with Fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using Fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.
Glycemic Control — In patients with diabetes, Fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with Fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with Fluoxetine is instituted or discontinued.
Acute Narrow-Angle Glaucoma—Mydriasis has been reported in association with Fluoxetine; therefore, caution should be used when prescribing Fluoxetine in patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma.
Potential for Cognitive and Motor Impairment
As with any CNS-active drug, Fluoxetine has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.
Long Elimination Half-Life
Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with Fluoxetine and norFluoxetine following the discontinuation of Fluoxetine [see Clinical Pharmacology (12.3)].
Discontinuation of Treatment
During marketing of Fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma Fluoxetine and norFluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.
Multiple doses of Fluoxetine had been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered Fluoxetine in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories.
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed. An adverse reaction was included if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that adverse reactions reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of adverse reactions 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 MDD, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common adverse reactions associated with the use of Fluoxetine (incidence of at least 5% for Fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of MDD, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.
Table 2. Most Common Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive-Compulsive Disorder, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials
Note: Includes U.S. data for MDD, OCD, bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials.
a = Denominator used was for males only (N = 690 Fluoxetine MDD; N = 410 placebo MDD; N = 116 Fluoxetine OCD; N = 43 placebo OCD; N = 14 Fluoxetine Bulimia; N = 1 placebo Bulimia; N = 162 Fluoxetine Panic Disorder; N = 121 placebo Panic Disorder).
-- = Incidence less than 1%. |
| |
Percentage of Patients Reporting Event |
| |
MDD |
OCD |
Bulimia |
Panic Disorder |
Body System/
Adverse Reaction |
Fluoxetine
(N = 1728) |
Placebo
(N = 975) |
Fluoxetine
(N = 266) |
Placebo
(N = 89) |
Fluoxetine
(N = 450) |
Placebo
(N = 267) |
Fluoxetine
(N = 425) |
Placebo
(N = 342) |
| Body as a Whole |
|
|
|
|
|
|
|
|
| Asthenia |
9 |
5 |
15 |
11 |
21 |
9 |
7 |
7 |
| Flu Syndrome |
3 |
4 |
10 |
7 |
8 |
3 |
5 |
5 |
| Cardiovascular System |
|
|
|
|
|
|
|
|
| Vasodilatation |
3 |
2 |
5 |
-- |
2 |
1 |
1 |
-- |
| Digestive System |
|
|
|
|
|
|
|
|
| Nausea |
21 |
9 |
26 |
13 |
29 |
11 |
12 |
7 |
| Diarrhea |
12 |
8 |
18 |
13 |
8 |
6 |
9 |
4 |
| Anorexia |
11 |
2 |
17 |
10 |
8 |
4 |
4 |
1 |
| Dry Mouth |
10 |
7 |
12 |
3 |
9 |
6 |
4 |
4 |
|
