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Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Anyone considering the use of fluoxetine or any other antidepressant in a child, adolescent or a young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond 24 years old; there was a reduction in risk with antidepressants compared to placebo in adults 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluoxetine is approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD).
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 disorder, and these disorders themselves are the strongest predictors of suicide. There has been 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.
Symptoms such as 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.
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 other symptoms described previously, as well as the emergence of suicidalilty, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions of fluoxetine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania: Bipolar disorder may present initially as a major depressive episode. It is thought that treating such an episode with an antidepressant alone may precipitate 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. Careful screening entails accurate recording of the patient's psychiatric history, particularly family history of suicide, bipolar disorder and depression. It should be noted that fluoxetine and olanzapine combination is approved for the acute treatment of depressive episodes associated with bipolar I disorder. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
Rash and Allergic Events: Fluoxetine has been reported to cause rash and/or urticaria, which may be associated with fever, leukocytosis, arthralgia, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. These symptoms usually resolve upon discontinuation of the drug and/or adjunctive treatment with antihistamines or steroids. There are also rare reports of patients who developed serious cutaneous systemic illnesses, identified to be leukocytoclastic vasculitis, vasculitis, erythema multiforme, and serum sickness. Since fluoxetine's introduction, predisposed patients with rash have developed lupus-like syndrome. Such untoward effects are rare but may be life-threatening as these severely affect the lung, kidney or liver. Anaphylactoid events (either alone or in combination) including bronchospasm, angioedema, laryngospasm, and urticaria have been reported. There have been rare reports of pulmonary events including inflammatory processes of varying histopathology and/or fibrosis. Fluoxetine should be discontinued in cases where a patient develops rash that appears to have no other probable cause.
Serotonin Syndrome: SSRIs such as fluoxetine, and serotonin and SNRIs can cause potentially fatal serotonin syndrome, particularly when taken together with other serotonergic drugs (such as triptans) and agents which inhibit the degradation of serotonin (MAOIs). Characteristic symptoms of serotonin syndrome 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). In cases where concurrent administration of a triptan and fluoxetine is needed, close therapeutic monitoring is important particularly during initial treatment and dosing shifts (increase or decrease). The coadministration of fluoxetine and serotonin precursors (such as tryptophan) is strongly discouraged.
Abnormal bleeding: SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk. Bleeding events associated with use of SSRIs and SNRIs include ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Anxiety and Insomnia: Clinical trials have reported that fluoxetine can cause anxiety, nervousness or insomnia. These adverse events have been associated with the highest incidence of fluoxetine therapy discontinuation.
Altered Appetite and Weight: Significant weight loss, particularly in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.
Activation of Mania/Hypomania: Clinical trials have documented that a small portion of patients manifested symptoms of mania/hypomania.
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluoxetine. This appears to be the result of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. There have been reports of serum sodium lower than 110 mmol/L and appeared to be reversible upon fluoxetine discontinuation. Elderly patients are at greater risk of developing hyponatremia with SSRIs and SNRIs including patients taking diuretics or who are volume-depleted. Discontinue fluoxetine use 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.
Seizures: Fluoxetine should be used with caution in patients with a history of convulsive disorder. Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency. Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored.
Akathisia: The use of fluoxetine has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. Increasing the dose may be detrimental in patients who develop these symptoms.
Long Elimination Half-Lives of Fluoxetine and its Metabolites: The full effect of dose titration and drug withdrawal will not be immediately apparent because of the relatively slow elimination of fluoxetine and its metabolites.
Use in Patients with Concomitant Illness: Caution should be exercised when prescribing fluoxetine to patients with diseases or conditions that affect metabolism or hemodynamic responses. Fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed after discontinuation of the drug. As is true with many other types of drugs 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.
Interference with Cognitive and Motor Performance: Patients should be warned that psychoactive drugs may impair judgment, thinking or motor skills. They should be advised to avoid tasks which require complete mental alertness such as operating hazardous machinery and driving vehicles until they are sure that their treatment does not significantly impede their ability to perform such activities.
Use in Children: Clinical trials have demonstrated fluoxetine's efficacy in treating MDD among pediatric patients 8 to ≤18 years old. It has also been shown to be effective in the treatment of OCD in pediatric patients 7 to <18 years old.
Fluoxetine has not been proven to be safe and effective for use in pediatric patients <8 years old with MDD and <7 years old with OCD. It is not approved for use in pediatric patients with bulimia nervosa, panic disorder and PMDD.
Use in Elderly: Fluoxetine's safety and efficacy in geriatric patients have been established. There is no significant difference in the drug's pharmacologic profile between the elderly and younger patient groups, but some older individuals may exhibit greater sensitivity. Hyponatremia caused by fluoxetine may be clinically significant for this population and monitoring is necessary.
