PAI Holdings, LLC dba PAI Pharma
Fluoxetine hydrochloride
GenericGeneric for Fluoxetine
ID: 00121072104
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TL;DR â Quick Summary
Key facts from the full medication guide below
đŠēWhat it's for
Fluoxetine is indicated for the treatment of: Acute and maintenance treatment of Major Depressive Disorder [ see Clinical Studies (14.1) ]. Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD) [ see Clinical Studies (14.2) ]. Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [ see Clinical Studies (14.3) ].
đHow to take it
Indication Adult Pediatric MDD ( 2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD ( 2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa ( 2.3) 60 mg/day in am - Panic Disorder ( 2.4) 10 mg/day (initial dose) - A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2.7)
âšī¸Common side effects
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.
â ī¸Serious risks
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behaviors with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. [see Warnings and Precautions (5.1)].
đInteractions & cautions
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.
đĻStorage & missed dose
Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Protect from light.
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Fluoxetine hydrochloride (Fluoxetine) Prices
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Warnings and Precautions, Serotonin Syndrome (5.2) 6/2023 Warnings and Precautions (5.7) 6/2023
Fluoxetine is indicated for the treatment of: Acute and maintenance treatment of Major Depressive Disorder [ see Clinical Studies (14.1) ]. Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD) [ see Clinical Studies (14.2) ]. Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [ see Clinical Studies (14.3) ]. Acute treatment of Panic Disorder, with or without agoraphobia [ see Clinical Studies (14.4) ]. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression. Fluoxetine is a selective serotonin reuptake inhibitor indicated for: Acute and maintenance treatment of Major Depressive Disorder (MDD) ( 1) Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) ( 1) Acute and maintenance treatment of Bulimia Nervosa ( 1) Acute treatment of Panic Disorder, with or without agoraphobia ( 1)
Indication Adult Pediatric MDD ( 2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD ( 2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa ( 2.3) 60 mg/day in am - Panic Disorder ( 2.4) 10 mg/day (initial dose) - A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2.7)
Initial Treatment Ad u l t - Initiate fluoxetine 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day. 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 [see Clinical Studies (14.1)] . Pediatric (children and adolescents) - Initiate fluoxetine 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose 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. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. 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 Studies (14.1) ]. A l l 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. Periodically reassess to determine the need for maintenance treatment. S witching 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 Warnings and Precautions (5.2) and Drug Interactions (7.7)] .
Advise patients that use of fluoxetine may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.16)].
Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.15)] .
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)] .
Do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)] . In some cases, a patient already receiving fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [ see Warnings and Precautions (5.2)] . The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluoxetine is unclear. The healthcare provider should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)] .
20 mg per 5 mL Liquid, Oral Solution with spearmint flavor Oral solution: 20 mg per 5 mL ( 3)
Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine. Do not use fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue ( 4.1) Pimozide: Do not use. Risk of QT prolongation and drug interaction ( 4.2, 5.11, 7.7, 7.8) Thioridazine: Do not use. Risk of QT interval prolongation and elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine ( 4.2, 5.11, 7.7, 7.8)
The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)] . Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.10) and Warnings and Precautions (5.2)] .
The use of fluoxetine is contraindicated with the following: Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)] Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)] Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue fluoxetine and serotonergic agents and initiate supportive treatment. If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. ( 5.2) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena ( 5.3) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania ( 5.4) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold ( 5.5) Altered Appetite and Weight: Significant weight loss has occurred ( 5.6) Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.8) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs ( 5.9) Anxiety and Insomnia: May occur ( 5.10) QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation ( 4.2, 5.11) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery ( 5.13) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.14) Sexual Dysfunction: Fluoxetine may cause symptoms of sexual dysfunction ( 5.16)
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 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 18-24) 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 4,400 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 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 Warnings and Precautions (5.15) ]. 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 liquid consistent with good patient management, in order to reduce the risk of overdose.
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI . The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.9, 2.10)] . If concomitant use of fluoxetine with other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with fluoxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.Treatment with fluoxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
In US 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.
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. In US placebo-controlled clinical trials for Major Depressive Disorder, 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 Major Depressive Disorder [see Use in Specific Populations (8.4)] . In US 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 US placebo-controlled clinical trials for bulimia. In US fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)] .
In US placebo-controlled clinical trials for Major Depressive Disorder, 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 US placebo-controlled clinical trials for either OCD or bulimia. In US 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 Major Depressive Disorder. Fluoxetine should be introduced with care in patients with a history of seizures.
Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine. In US placebo-controlled clinical trials for Major Depressive Disorder, 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 US 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 US 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.
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. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. 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 increased risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)] .
Angle-Closure Glaucoma - The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
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.
In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In US 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 US 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 US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 4].
Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications (4.2), Adverse Reactions (6.2), Drug Interactions (7.7, 7.8), Overdosage (10.1), and Clinical Pharmacology (12.3)] . Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3)] . Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.
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. G l yc emi c 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.
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.
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)] .
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 healthcare provider 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.
Use of SSRIs, including fluoxetine, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of fluoxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.
The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2)] Allergic Reactions and Rash [see Warnings and Precautions (5.3)] Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4)] Seizures [see Warnings and Precautions (5.5)] Altered Appetite and Weight [see Warnings and Precautions (5.6)] Abnormal Bleeding [see Warnings and Precautions (5.7)] Angle-Closure Glaucoma [see Warnings and Precautions (5.8)] Hyponatremia [see Warnings and Precautions (5.9)] Anxiety and Insomnia [see Warnings and Precautions (5.10)] QT Prolongation [see Warnings and Precautions (5.11)] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)] Discontinuation Adverse Reactions [see Warnings and Precautions (5.15)] Most common adverse reactions ( 5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pharmaceutical Associates, Inc., at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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 have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. In c id e n c e in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) - Table 2 enumerates the most common treatment-emergent 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 Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials. Table 4 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.
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. Monoamine Oxidase Inhibitors (MAOIs): ( 2.9, 2.10, 4.1, 5.2) Drug s Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.7) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued ( 5.2, 7.7) CN S Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs ( 7.2) Benzodiazepines: Diazepam increased t , alprazolam - further psychomotor performance decrement due to increased levels ( 7.7) Antipsychotics: Potential for elevation of haloperidol and clozapine levels ( 7.7) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity ( 7.7) Serotonergic Drugs: ( 2.9, 2.10, 4.1, 5.2) Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding ( 7.4) Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations ( 7.6, 7.7) Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval ( 4.2, 5.11, 7.7, 7.8)
[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].
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 Clinical Pharmacology (12.3)].
[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].
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 may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)].
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.
Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].
Pregnancy: SSRI use, particularly later in pregnancy, may increase risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1) Pediatric Use: Safety and effectiveness of fluoxetine in patients <8 years of age with Major Depressive Disorder and <7 years of age with OCD have not been established. ( 8.4) Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis ( 8.6)
Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants/. Non-teratogenic Effects Risk Summary Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.2)]. Available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. Some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data). There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). In rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m2 basis. However, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 time (during gestation and lactation) the MRHD given to adolescents on a mg/m2 basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal adverse reactions Neonates exposed to fluoxetine and other SSRI or 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, tremors, jitteriness, irritability, and constant crying. These findings 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 Warnings and Precautions (5.2)]. Data Human Data - It has been shown that SSRIs (including fluoxetine) can cross the placenta. Published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data - In embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.6 and 3.9 times, respectively, the MRHD of 60 mg given to adolescents on a mg/m2 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 given to adolescents on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.97 time the MRHD given to adolescents on a mg/m2 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 (0.65 time the MRHD given to adolescents on a mg/m2 basis). Maternal Adverse Reactions Use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.7).
Risk Summary Data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk (see Clinical Considerations). There are no data on the effect of fluoxetine or its metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for fluoxetine and any potential adverse effects on the breastfed child from fluoxetine or the underlying maternal condition. Clinical Considerations Infants exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain. Data A study of 19 nursing mothers on fluoxetine with daily doses of 10-60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL).
Use of fluoxetine in children - 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 Studies (14.1)]. 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 Studies (14.2)]. 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 or OCD [see Clinical Pharmacology (12.3)]. The acute adverse reaction 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 reaction 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 (6.1)]. 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 and 1.1 kg less in weight 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 and Precautions (5.6)]. Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. Animal Data - Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5-10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1-2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1-0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3-0.8, 1-8, and 3-20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.
US 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 Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. 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. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)].
In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)].
Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1,578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette's syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as nodal rhythm QT interval prolongation and ventricular arrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.
Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)].
For current information on the management of fluoxetine overdose, contact a certified poison control center (1-800-222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. 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 Drug Interactions (7.7)].
Fluoxetine Oral Solution USP is a selective serotonin reuptake inhibitor 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-[( , , -trifluoro- p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C 17H 18F 3NO 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. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg per 5 mL (64.7 mol) of fluoxetine. It also contains the following inactive ingredients: glycerin, purified water, sodium benzoate, spearmint flavoring agent, and sucrose, and may contain hydrochloric acid and/or sodium hydroxide to adjust the pH.
Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.
Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and 1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.
Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.
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 3 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 3 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 3 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 1 to 2 episodes per week for binge-eating and 2 to 4 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.
The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 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.
Fluoxetine Oral Solution USP (20 mg per 5 mL), a clear to pale yellow liquid with spearmint flavor, is available in the following oral dosage forms: NDC 0121-0721-04: 4 fl oz (120 mL) bottle NDC 0121-4721-05: 5 mL unit dose cup NDC 0121-4721-40: Case contains 40 unit dose cups of 5 mL (0121-4721-05) packaged in 4 trays of 10 unit dose cups each. Dispense in a tight, light-resistant container.
Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Protect from light.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
MANUFACTURED BY PAI Pharma Greenville, SC 29605 www.paipharma.com R08/23
Read the Medication Guide that comes with fluoxetine before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about fluoxetine? Fluoxetine and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Fluoxetine and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when fluoxetine is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine may be associated with these serious side effects: 2. Serotonin Syndrome. This condition can be life-threatening and may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity dizziness flushing tremor seizures 3. Severe allergic reactions: trouble breathing swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain 4. Abnormal bleeding: Fluoxetine and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin , Jantoven ), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. Visual Problems: eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. 6. Seizures or convulsions 7. Manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment. 9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include: fast, slow, or irregular heartbeat shortness of breath dizziness or fainting Do not stop fluoxetine without first talking to your healthcare provider. Stopping fluoxetine too quickly may cause serious symptoms including: anxiety, irritability, high or low mood, feeling restless or changes in sleep habits headache, sweating, nausea, dizziness electric shock-like sensations, shaking, confusion 11. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, may cause sexual problems. Symptoms in males may include: Delayed ejaculation or inability to have an ejaculation Decreased sex drive Problems getting or keeping an erection Symptoms in females may include: Decreased sex drive Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluoxetine. There may be treatments your healthcare provider can suggest. What is fluoxetine? Fluoxetine is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Fluoxetine is used to treat: Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Bulimia Nervosa* Panic Disorder* *Not approved for use in children. Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine treatment. Who should not take fluoxetine? Do not take fluoxetine if you: are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine oral solution. See the end of this Medication Guide for a complete list of ingredients in fluoxetine oral solution. take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 5 weeks of stopping fluoxetine unless directed to do so by your physician. Do not start fluoxetine if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take fluoxetine close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) take Mellaril (thioridazine). Do not take Mellaril within 5 weeks of stopping fluoxetine because this can cause serious heart rhythm problems or sudden death. take the antipsychotic medicine pimozide (Orap ) because this can cause serious heart problems. What should I tell my healthcare provider before taking fluoxetine? Ask if you are not sure. Before starting fluoxetine, tell your healthcare provider if you: Are taking certain drugs or treatments such as: Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics Amphetamines Tramadol and fentanyl Meperidine Methadone Or other opioids Over-the-counter supplements such as tryptophan or St. John's Wort Electroconvulsive therapy (ECT) have liver problems have kidney problems have heart problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have a history of a stroke have high blood pressure have or had bleeding problems are pregnant or plan to become pregnant. It is not known if fluoxetine will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. are breast-feeding or plan to breast-feed. Some fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fluoxetine and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine with your other medicines. Do not start or stop any medicine while taking fluoxetine without talking to your healthcare provider first. If you take fluoxetine, you should not take any other medicines that contain fluoxetine hydrochloride including: *Symbyax *Sarafem *PROZAC Weekly How should I take fluoxetine? Take fluoxetine exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine until it is the right dose for you. Fluoxetine may be taken with or without food. If you miss a dose of fluoxetine, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluoxetine at the same time. If you take too much fluoxetine, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking fluoxetine? Fluoxetine can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluoxetine affects you. Do not drink alcohol while using fluoxetine. What are the possible side effects of fluoxetine? Fluoxetine may cause serious side effects, including: See " What is the most important information I should know about fluoxetine?" Problems with blood sugar control. People who have diabetes and take fluoxetine may have problems with low blood sugar while taking fluoxetine. High blood sugar can happen when fluoxetine is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine. Feeling anxious or trouble sleeping Common possible side effects in people who take fluoxetine include: unusual dreams sexual problems loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth flu symptoms feeling tired or fatigued change in sleep habits yawning sinus infection or sore throat tremor or shaking sweating feeling anxious or nervous hot flashes rash Other side effects in children and adolescents include: increased thirst abnormal increase in muscle movement or agitation nose bleed urinating more often heavy menstrual periods possible slowed growth rate and weight change. Your child's height and weight should be monitored during treatment with fluoxetine. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluoxetine. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store fluoxetine? Store fluoxetine at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Keep fluoxetine away from light. Keep fluoxetine bottle closed tightly. Keep fluoxetine and all medicines out of the reach of children. General information about fluoxetine Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine for a condition for which it was not prescribed. Do not give fluoxetine to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about fluoxetine. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine that is written for healthcare professionals. For more information about fluoxetine call 1-800-845-8210 or visit www.paipharma.com. What are the ingredients in fluoxetine oral solution USP? Active ingredient: fluoxetine hydrochloride Inactive ingredients: glycerin, purified water, sodium benzoate, spearmint flavoring agent, and sucrose, and may contain hydrochloric acid and/or sodium hydroxide to adjust the pH. *Prozac Weekly, Symbyax and Sarafem are registered trademarks of Eli Lilly and Company R08/23 MG072110823 PAI Pharma Greenville, SC 29605 www.paipharma.com This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide revised, August 2023
NDC 0121-0721-04 Fluoxetine Oral Solution USP 20 mg/5 mL PHARMACIST: Provide accompanying Medication Guide to patient or caregiver a the time of dispensing. Rx ONLY 120 mL Pharmaceutical Associates, Inc. Greenville, SC 29605
Fluoxetine Oral Solution USP 20 mg per 5 mL Rx ONLY 120 mL Package Not Child-Resistant Pharmaceutical Associates, Inc. Greenville, SC 29605
