FLUOXETINE DR

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be administered without regard to meals.
Oral Solid Formulations
Immediate-release capsules or tablets:
-Initially, administer in the morning.
-Doses greater than 20 mg/day may be taken as a single daily dose or divided into 2 doses (e.g., in the morning and at noon).

Delayed-Release capsules (e.g., Prozac Weekly):
-Administer on the same day of the week each week.
-Patients should swallow the capsule whole; do not crush, cut, or chew.
-NOTE: The fluoxetine once-weekly formulation is not approved by the FDA for use in pediatric patients.

Oral Liquid Formulations
Oral solution:
-To ensure accurate dosing, measure dosage with a calibrated oral liquid measuring device.
-Initially, administer in the morning. May give with or without food.
-Doses greater than 20 mg/day may be administered as a single daily dose or divided into 2 doses (e.g., in the morning and at noon).

Gastrointestinal effects are among the most frequently reported adverse reactions with SSRIs. Clinical data from all conditions studied indicate that nausea (12% to 29%), diarrhea (8% to 18%), anorexia (4% to 17%), xerostomia (4% to 12%), dyspepsia (6% to 10%), constipation (5%), flatulence (3%), vomiting (3%), and weight loss (2%). Polydipsia was reported in pediatric patients receiving fluoxetine at an incidence of at least 2% and at a rate which was greater than placebo. Nausea usually subsides after a few weeks of therapy but occasionally is severe enough to necessitate discontinuation of the drug. Many gastrointestinal effects appear to be dose-related and respond to a dosage reduction in most patients. Appetite stimulation, weight gain, and dysgeusia occurred in 1% or more of patients evaluated. Aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, hypersalivation, oral ulceration, stomach ulcer, and stomatitis were reported infrequently (0.1% to 1%). Rare events (less than 0.1%) included acute abdominal syndrome with abdominal pain, biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulceration, fecal incontinence, GI hemorrhage, colon hemorrhage, GI obstruction, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, taste loss, and tongue swelling. Anorexia can result from serotonin-reuptake blockade, and tolerance to this effect does not appear to occur. In clinical practice, weight loss exceeding 5% of body weight has been reported in 10% to 15% of fluoxetine-treated patients; weight loss corresponds to increasing dose. Approximately 1% of patients require discontinuation due to this adverse effect. Periodically assess weight, especially in those who are underweight. Periodic monitoring of weight and height is recommended for all pediatric patients receiving fluoxetine.

Centrally-mediated effects are common with fluoxetine therapy. Clinical data from all conditions studied indicated insomnia (10% to 33%), drowsiness (5% to 17%), abnormal dreams (1% to 5%), headache (21%), dizziness (9%), and yawning (1% to 11%) occurred more frequently in those receiving fluoxetine than placebo. Unspecified sleep disorders, migraine, and paresthesias occurred in 1% or more of patients. Hypoesthesia, neuralgia, neuropathy (neuropathic pain), vertigo, and CNS stimulation were reported in 0.1 to 1% of patients. Rarely (less than 0.1%), EEG changes, circumoral paresthesia, hyperesthesia, and neuritis occurred. Fluoxetine can also cause drug-induced seizures, but they have been reported at a very low frequency (12 of 6,000 patients), unless preceded by overdose or in the presence of a preexisting seizure disorder.

During clinical evaluation, hyperkinesis was reported in pediatric patients receiving fluoxetine at an incidence of at least 2% and at a rate which was greater than placebo. Clinical data from all conditions studied indicated tremor (3% to 13%) occurred more frequently in those receiving fluoxetine than placebo. Akathisia, ataxia, balance disorder, teeth grinding (bruxism), tardive dyskinesia (buccoglossal syndrome), hypertonia, myoclonia, incoordination, and abnormal gait occurred infrequently in 0.1% to 1% of patients during clinical evaluation. Rarely (less than 0.1%), dysarthria, dystonia or dystonic reaction, extrapyramidal symptoms, foot drop, muscle paralysis, torticollis, and hyporeflexia were reported. Dyskinesia, worsening of movement disorders, and development of movement disorders in patients with risk factors have been also been reported postmarketing. Dyskinesia has been documented to include a patient who developed buccal-lingual-masticatory syndrome with involuntary tongue protrusion which resolved a few months after drug discontinuation.

Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. Agitation and personality disorder were reported in pediatric patients receiving fluoxetine at an incidence of at least 2% and at a greater frequency than with placebo during clinical trials. Clinical data from all conditions studied indicated anxiety (6% to 15%), nervousness (8% to 14%), and abnormal thinking (2%) occurred more frequently in those receiving fluoxetine than placebo. Emotional lability and amnesia occurred in 1% or more of patients. Depersonalization, euphoria, paranoia, acute brain syndrome, apathy, hostility, worsening of depression, suicide attempt, intentional overdose, neurosis, and psychosis were reported in 0.1% to 1% of patients. Rarely (less than 0.1%), delusions (hallucinations), antisocial reaction, confusion, intentional injury, and stupor occurred. Unspecified violent behavior, memory impairment, and suicidal ideation have been reported postmarketing. Antidepressants can precipitate hypomania or mania in susceptible individuals. Mania/hypomania was reported in 2.6% of pediatric patients treated with fluoxetine during clinical trials and was responsible for drug discontinuation in 1.8% of patients. Manic symptoms and suicidal ideation appear to be more prevalent in children with or at high risk for bipolar disorder on antidepressants; monitor such patients closely. In a study of 52 patients (mean age: 15 years, range: 7 to 22 years) with bipolar disorder or subthreshold manic symptoms and exposure to antidepressants, 50% developed antidepressant-induced mania and 25.5% had new-onset suicidal ideation.

Platelet dysfunction (i.e., impaired platelet aggregation) may occur during treatment with selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., GI bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage). During clinical evaluation, epistaxis was reported in pediatric patients receiving fluoxetine at an incidence of at least 2% and at a rate which was greater than placebo. Anemia and ecchymosis were reported in 0.1% to 1% of adult patients receiving fluoxetine during pre-marketing evaluation. Rare events (less than 0.1%) included blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechiae, purpura, thrombocythemia, thrombocytopenia, gum hemorrhage, bloody diarrhea, melena, GI bleeding, hematemesis, colon hemorrhage, rectal hemorrhage, and peptic ulcer hemorrhage. During postmarketing use, aplastic anemia, immune-related hemolytic anemia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP) have been reported; however, the frequencies are unknown and causality to the drug has not been established. An increased risk of bleeding complications is possible in patients receiving antiplatelet or anticoagulant medications concurrently with fluoxetine.

Fluoxetine may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of fluoxetine. Patients receiving diuretics or prone to becoming dehydrated, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, fainting, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of the SSRI, as well as implementation of the appropriate medical interventions.

QT prolongation (QTcF 450 msec or more) occurred in 1% or more of patients receiving fluoxetine during clinical trials, based on routine ECG measurements. Additionally, ventricular arrhythmia (ventricular tachycardia including torsade de pointes) has been reported with postmarketing use. If patients at risk for QT prolongation and ventricular arrhythmia are initiated on fluoxetine, baseline and periodic ECG assessment are recommended. Discontinue fluoxetine and obtain prompt cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. During clinical trial evaluation, vasodilation or flushing (1% to 5%) occurred more frequently in adults receiving fluoxetine compared to those receiving placebo. Palpitations, chest pain (unspecified), and hypertension occurred in 1% or more of patients. Arrhythmia (arrhythmia exacerbation), hypotension, angina pectoris, congestive heart failure, myocardial infarction, orthostatic hypotension, syncope, vascular headache were reported in 0.1% to 1% of patients. Rarely, bradycardia, cerebral embolism, cerebral ischemia, extrasystoles, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, coronary vasospasm, ventricular extrasystoles, ventricular fibrillation occurred. Atrial fibrillation, cerebrovascular accident (stroke), cardiac arrest, and pulmonary hypertension have been reported postmarketing; however, incidence is unknown and causality to the drug has not been established.

General clinical data from all conditions studied indicate that asthenia occurred more frequently in those receiving fluoxetine than placebo (7% to 21%). Malaise, generalized edema, peripheral edema, and facial edema occurred in 0.1% to 1% of patients. Hypothermia was rarely reported.

Menorrhagia was reported in pediatric female patients receiving fluoxetine during clinical trials at a rate of at least 2% and greater than that of placebo. Reproductive or hormonal effects that were reported rarely (1% or less) during premarketing evaluation of fluoxetine included amenorrhea, breast enlargement, mastalgia, breast discharge, leukorrhea, fibrocystic breast, female lactation, menorrhagia, metrorrhagia, and vaginal bleeding. During postmarketing use, galactorrhea, gynecomastia, and hyperprolactinemia have been reported. Very rarely (less than 0.1.%), breast engorgement, hypomenorrhea, uterine hemorrhage, and enlarged uterine fibroids were reported in female patients. Priapism has been reported rarely with all of the SSRIs (rare, less than 0.1% of adult males). Because priapism is considered a medical emergency, fluoxetine should be discontinued if priapism develops and appropriate medical treatment should be promptly initiated.

In U.S. clinical trials of fluoxetine, 7% of 10,782 patients developed rash and/or urticaria. Clinical data from all conditions studied indicate that hyperhidrosis (2% to 8%), pruritus (3%), and rash (unspecified) (2% to 6%) occurred more frequently in fluoxetine-treated patients than those receiving placebo. Infrequently (0.1% to 1%), alopecia, acne vulgaris, atopic dermatitis, maculopapular rash, skin discoloration, or skin ulcer occurred. Photosensitivity reactions, purpuric rash, furunculosis, herpes zoster, hirsutism, psoriasis, and seborrhea were rarely (less than 0.1%) reported. During postmarketing, serious skin reactions including toxic epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, and Stevens-Johnson syndrome have been reported; however, the frequencies are unknown and causality to the drug has not been established. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of fluoxetine according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Fluoxetine should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified. All dermatological reactions should be investigated because they could be precursors of a serious systemic reaction to the drug. In most cases, maculopapular rash or urticaria disappears with treatment with an antihistamine or corticosteroid, or upon discontinuation of the drug. Anaphylactoid reactions, including angioedema, bronchospasm, laryngospasm, and urticaria, alone and in combination, have been reported during fluoxetine treatment. Patients have also had systemic syndromes suggestive of serum sickness. Since the introduction of fluoxetine, systemic events, possibly related to vasculitis and including lupus-like symptoms, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Pulmonary events, including inflammatory processes of varying histopathology and/or pulmonary fibrosis, have been reported rarely. Some of these events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause is not known; a specific underlying immunologic basis for these events has not been identified. If allergic phenomena occur for which an alternative etiology cannot be identified, fluoxetine should be discontinued.

Influenza-like syndrome (3% to 10%), pharyngitis (3% to 11%), sinusitis (1% to 6%), and fever (2%) occurred more frequently in fluoxetine-treated patients than those receiving placebo during adult clinical trials of fluoxetine. Chills were reported in 1% or more of patients; asthma, hiccups, hyperventilation were reported less frequently, in 0.1% to 1% of patients. Rarely, laryngeal edema, apnea, atelectasis, decreased cough, emphysema, hemoptysis, hypoventilation, hypoxia, pulmonary edema, pneumothorax, and stridor have occurred. Airway spasm or swelling may indicate allergic events. During postmarketing, eosinophilic pneumonia, anosmia, hyposmia, and pulmonary embolism have been reported; however, the frequencies are unknown and causality to the drug has not been established.

During clinical trial evaluation, visual impairment (abnormal vision 2%) occurred more frequently in those receiving fluoxetine than placebo. Other frequently reported (1% or more) adverse events affecting the special senses included dysgeusia, otalgia, and tinnitus. Mydriasis, conjunctivitis, xerophthalmia, and photophobia occurred in 0.1% to 1% of patients. Rare effects included ocular hypertension (angle-closure glaucoma), blepharitis, deafness (hearing loss), diplopia, exophthalmos, hyperacusis, iritis, parosmia, scleritis, strabismus, ageusia, and visual field defects. Optic neuritis and cataracts have been reported with postmarketing use; however, the frequency is unknown and causality to the drug has not been established.

Elevated hepatic enzymes were reported infrequently (0.1% to 1%) during premarketing evaluation of fluoxetine. Hepatitis and liver fatty deposit were reported rarely (less than 0.1%). During postmarketing, cholestatic jaundice, hepatic failure, and hepatic necrosis have been reported; however, the frequencies are unknown and causality to the drug has not been established.

Increased urinary frequency occurred at an incidence of 2% or more during clinical evaluation of fluoxetine in pediatric patients. In all fluoxetine trials, micturition was reported at a frequency of 1% or more; dysuria, albuminuria (proteinuria), cystitis, hematuria, nocturia, polyuria, urinary incontinence, urinary retention, and urinary urgency occurred less frequently in 0.1% to 1% of patients. Rarely (less than 0.1%), kidney pain (flank pain), glycosuria, and oliguria were reported. Renal failure (unspecified) has been reported in association with fluoxetine use postmarketing; however, the frequency is unknown and causality to the drug has not been established.

Fluoxetine may cause altered glycemic control, although this effect appears to be uncommon. Fluoxetine administration has been associated with diabetic ketoacidosis, diabetes mellitus, hyperglycemia, and hypoglycemia in rare instances. In addition, hypothyroidism was reported in 0.1% to 1% of fluoxetine-treated patients during clinical evaluation.

Metabolic and nutritional events, including laboratory alterations, which occurred infrequently (0.1% to 1%) during premarketing evaluation of fluoxetine included dehydration, gout, hypercholesterolemia, hyperlipidemia, and hypokalemia. Rarely reported effects (less than 0.1%) included alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, and iron deficiency anemia.

Arthritis with arthralgia, bone pain, bursitis, leg cramps (muscle cramps), pelvic pain, and synovitis (tenosynovitis) were reported infrequently (0.1% to 1%) during premarketing evaluation of fluoxetine. Rare events (less than 0.1%) included arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, and rheumatoid arthritis.

Osteoporosis was reported rarely (less than 0.1%) during premarketing evaluation of fluoxetine in adults. Use selective serotonin reuptake inhibitors (SSRIs) with caution in patients with osteopenia or risk factors for osteopenia. Epidemiological studies suggest an association between the use of SSRIs and bone fractures in adults. Some data suggest that chronic treatment with SSRIs, such as fluoxetine, may be associated with reduced bone density.

Serotonin syndrome has been reported during use of fluoxetine. Serotonin syndrome can occur from the use of SSRIs alone, during concurrent use of other medications known to increase CNS or peripheral serotonin levels, or during SSRI overdose. The long half-life and active metabolite of fluoxetine should be considered when investigating potential risks for serotonin syndrome. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. In its most severe form, serotonin syndrome may resemble neuroleptic malignant syndrome. If serotonin syndrome becomes evident during treatment, fluoxetine and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential withdrawal symptoms. Withdrawal symptoms have been reported with abrupt or rapid discontinuation of fluoxetine or other SSRIs. Withdrawal symptoms have included dysphoric mood, irritability, agitation, dizziness, paresthesias, headache, hypomania, anxiety, confusion, lethargy, emotional lability and insomnia. The most commonly reported SSRI withdrawal symptoms include fatigue, abdominal pain or nausea, dizziness/light-headedness, tremor, chills, diaphoresis, and incoordination. Withdrawal symptoms usually begin 1 to 3 days after abrupt discontinuation of the short-acting SSRI and remit within 1 to 2 weeks; although with fluoxetine this may be delayed due to the long half-life of the active metabolite. The difference in the incidence of withdrawal symptoms among SSRIs is most likely due to differences in the half-lives of the active moieties. Fluoxetine is a long-acting SSRI, and withdrawal symptoms are relatively uncommon due to the long half-life of the drug's active metabolite relative to other SSRIs.

A neonatal abstinence syndrome has been reported in infants exposed to serotonergic agents such as fluoxetine in utero, with features consistent with either a direct toxic effect of serotonergic agents (e.g., serotonin syndrome), or possibly a drug discontinuation syndrome. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) have been noted. Several other symptoms (bloody stools, necrotizing enterocolitis) may have been attributable to rebound platelet activation on withdrawal of SSRI exposure. Neonatal symptoms generally improve over several days. A cohort study revealed that 22% of neonates exposed to an SSRI in the third trimester had complications requiring treatment or extended hospitalization compared with 6% in comparison groups. Other potential adverse events have also been reported, including a potential association between maternal use of SSRIs in the third trimester and the development of persistent pulmonary hypertension of the newborn (PPHN). Some retrospective studies have not shown an increased risk of PPHN with SSRI exposure. The FDA has stated that an increased risk of PPHN from SSRI exposure cannot be determined due to conflicting data.

As with other SSRIs, decreased weight gain has been observed in children and adolescents receiving fluoxetine. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition, but height and weight should be monitored periodically throughout therapy. In a fluoxetine clinical trial, children and adolescents 9 to 17 years gained about 1.1 cm less in height and about 1 kg less in weight, after 19 weeks of treatment, compared to pediatric patients treated with placebo. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.

Avoid abrupt discontinuation of any SSRI if possible. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential withdrawal symptoms. However, withdrawal symptoms have been reported less frequently with long-acting SSRIs such as fluoxetine than short-acting SSRIs such as paroxetine. Symptoms associated with abrupt withdrawal of fluoxetine have included dysphoric mood, irritability, agitation, dizziness, paresthesias, and headache.

Fluoxetine should be used with caution in patients with a seizure disorder. Seizures have been reported rarely in patients taking fluoxetine; however, they have occurred primarily in cases of fluoxetine overdose. Fluoxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date. Some clinicians have reported that in rare instances ECT-induced seizures were prolonged in patients taking fluoxetine. A possible mechanism of seizure prolongation may be a lowering of the seizure threshold caused by high concentrations of fluoxetine or its active metabolite norfluoxetine.

Fluoxetine is not FDA-approved for use in pediatric patients younger than 7 years of age. Antidepressants increased the risk of suicidal thoughts and behavior in children and adolescents in short-term studies. Prescribe fluoxetine in the smallest quantity consistent with good patient management to reduce the risk of overdose. Monitor all patients receiving antidepressants for any indication closely for clinical worsening, suicidal ideation, and unusual behavioral changes, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania, especially during the first few months of therapy and after any dosage adjustment. Instruct caregivers and patients to immediately notify the prescriber of changes in behavior or suicidal ideation. Consider changing the therapeutic regimen or discontinuing the medication in patients with persistent or worrisome symptoms, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. In a pooled analysis of placebo-controlled trials of antidepressants (n = more than 4,400 pediatric patients and 77,000 adult patients), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. It is unknown if the suicidality risk extends to long-term use (i.e., more than 4 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, a known risk factor for suicidal thoughts and behaviors.

Mania or hypomania can be precipitated in predisposed individuals during treatment with an antidepressant, including fluoxetine. Children with a family history of bipolar disorder, those who have a diagnosis of bipolar disorder, and those with subthreshold manic symptoms may be at increased risk for developing mania during treatment. In addition, patients with pre-existing bipolar disorder type I, compared to those with subsyndromal or type II bipolar disorder, and those with psychiatric comorbidities may be at increased risk for antidepressant-induced mania. Younger patients may be more likely to experience antidepressant-induced mania. Suicidal ideation appears to be more prevalent in children with or at high risk for bipolar disorder on antidepressants. In a study of 52 patients (mean age of 15 years, ranging from 7 to 22 years) with bipolar disorder or subthreshold manic symptoms, 25.5% had new-onset suicidal ideation within the first 3 months of antidepressant use. Progressive evaluation of youth at risk for bipolar disorder who were exposed to antidepressants (n = 21; age range of 9 to 20 years) suggested psychiatric adverse events such as irritability, aggression, impulsivity, and hyperactivity were more common in younger patients. A major depressive episode may be the initial presentation of bipolar disorder. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder prior to initiating treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. The response of patients with a previously established history of bipolar disorder should be closely monitored if therapy with an antidepressant is indicated.

Use fluoxetine with caution in patients with hepatic disease; the elimination half-lives of fluoxetine and norfluoxetine are significantly prolonged in patients with cirrhosis. In addition, because fluoxetine treatment has been associated with prolongation of the QTc interval and significant arrhythmias, caution is advisable when using fluoxetine in patients with conditions that predispose to increased fluoxetine exposure such as hepatic impairment. If fluoxetine is administered to a patient with hepatic impairment, a lower dose or less frequent dosing interval should be used.

QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported in patients treated with fluoxetine. If patients at risk for QT prolongation and ventricular arrhythmia are initiated on fluoxetine, baseline and periodic ECG assessment are recommended. Discontinue fluoxetine and obtain prompt cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. Use fluoxetine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, concurrent medications known to prolong the QT interval, or patients at risk for a significant electrolyte imbalance (e.g., diuretic therapy, diarrhea). Correct electrolyte imbalances prior to initiating treatment. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. In addition, conditions that predispose patients to increased fluoxetine exposure (e.g., overdose, CYP2D6 poor metabolizers, concomitant use of CYP2D6 inhibitors or highly protein-bound drugs) may put patients at risk.

Selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of the SSRI, as well as implementation of the appropriate medical interventions.

Monitor patients taking an SSRI, like fluoxetine, for signs and symptoms of bleeding. Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients or their caregivers should be instructed to promptly report any bleeding events to the practitioner.

Caution is recommended when prescribing fluoxetine to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

Because any psychoactive drug may impair judgment, thinking, or motor skills, patients should use caution when engaging in activities requiring coordination and concentration, including driving or operating machinery, until they are reasonably certain that fluoxetine does not affect them.

In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy, 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, the dose of insulin and/or oral hypoglycemic medication may need to be adjusted when therapy with fluoxetine is initiated or discontinued.

Decreased appetite and weight loss have been observed during the administration of SSRIs. Therefore, caution is advisable when administering fluoxetine to patients with anorexia nervosa or other conditions where weight loss is undesirable. Regular monitoring of weight and growth is recommended in children and adolescents treated with fluoxetine.

Fluoxetine is contraindicated with concurrent use of MAOI therapy intended to treat psychiatric disorders because of an increased risk of serotonin syndrome. At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and fluoxetine initiation. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting a MAOI intended to treat psychiatric disorders. Starting fluoxetine in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated because of an increased risk of serotonin syndrome. If acceptable alternatives are not available and benefits are judged to outweigh the risks of serotonin syndrome, fluoxetine should be promptly discontinued before initiating treatment with linezolid or methylene blue. Monitor the patient closely for symptoms of serotonin syndrome for 5 weeks after discontinuing fluoxetine or until 24 hours after the last dose of linezolid or methylene blue, whichever comes first. Therapy with fluoxetine may be resumed 24 hours after the last dose of linezolid or methylene blue. Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort). If such symptoms occur, discontinue the SSRI and other serotonergic drugs 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.

Neonates with in utero exposure to SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs, a drug discontinuation syndrome, or serotonin syndrome. In addition, although available data are conflicting, some epidemiologic reports suggest an association between maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn (PPHN). Because PPHN is associated with significant morbidity and mortality, it is important that practitioners are aware of antidepressant exposure to avoid delays in diagnosis and treatment. In a meta-analysis of 7 studies, there was a small but significant association between SSRI exposure in late pregnancy and PPHN; effects were not significant for other variables examined (e.g., study design, congenital malformations, meconium aspiration). Effects of caesarian delivery, maternal body mass index, and preterm delivery were not assessed. PPHN occurs in approximately 1.9 of 1,000 live births in the general population and is a relatively uncommon event; based on this analysis it is estimated that an average of 1 associated case of PPHN would result from 286 to 351 women being treated with an SSRI during late gestation.

The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy. Monitor height and weight periodically while the patient is receiving fluoxetine. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving fluoxetine. In a fluoxetine clinical trial, children and adolescents 9 to 17 years gained about 1.1 cm less in height and about 1 kg less in weight, after 19 weeks of treatment, compared to pediatric patients treated with placebo. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.

Description: Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) indicated for treating major depressive disorder (MDD) and anxiety disorders. Fluoxetine was the first SSRI to receive approval in pediatric patients 8 years and older with MDD and is the most extensively evaluated SSRI in pediatric depression. Fluoxetine is also FDA approved for the treatment of obsessive-compulsive disorder (OCD) in pediatric patients 7 years and older. Clinical guidelines and treatment algorithms describe a role for SSRIs in the treatment of childhood depression, with fluoxetine considered a first-line therapy. In addition, SSRIs are considered first-line therapy for childhood anxiety disorders requiring pharmacologic treatment, although few indications are FDA approved, and long-term safety and efficacy data are limited. Fluoxetine is a potent inhibitor of CYP2D6, which can result in clinically significant interactions with CYP2D6 substrates. Product labels for all antidepressants contain a warning related to an increased risk of suicidality in children and adolescents during the initial stages of therapy when treating depression or other conditions; therefore, the necessity of pharmacologic therapy versus the potential risks should be carefully considered in the pediatric population.

For the treatment of major depression:
Oral dosage (immediate-release):
Children and Adolescents 8 to 17 years: 10 or 20 mg PO once daily, initially; an initial dose of 10 mg/day may be appropriate in lower weight children. Increase dose to 20 mg/day after 1 week and may increase the dose after several weeks if inadequate response and depending on tolerability. May divide doses of 20 mg/day or more in 2 doses (e.g., morning and noon). Usual dose: 10 to 20 mg/day. Max: 60 mg/day. Periodically reassess the need for continued treatment.

For the treatment of obsessive-compulsive disorder (OCD):
Oral dosage (immediate-release capsules, tablets, or oral solution; e.g., Prozac):
Children 3 to 6 years*: Data are limited. 5 mg/day PO initially, followed by gradual increases based on response to a range of 5 to 15 mg/day may be effective in preschool children with OCD resistant to nonpharmacologic treatment and symptoms and functional impairment that are severe. Behavioral disinhibition has occurred in some preschool children receiving doses of 15 to 20 mg/day. These adverse behavioral symptoms have resolved after dose reductions. Further study assessing safety and efficacy is necessary.
Children and Adolescents 7 to 17 years: 10 mg/day PO initially. In higher weight pediatric patients, increase to 20 mg/day after 2 weeks; may increase the dosage after several more weeks if insufficient response. Target dosage (higher weight): 20 to 60 mg/day PO. In lower weight children, the initial 10 mg dosage may be increased after several weeks if insufficient response observed. Target dosage (lower weight): 20 to 30 mg/day PO.

For the treatment of panic disorder*, with or without agoraphobia*:
Oral dosage (immediate-release capsules, tablets, or oral solution; e.g., Prozac):
Children and Adolescents 8 to 17 years: Usual starting dose is 10 mg/day PO, followed by titration after several weeks. Published data are extremely limited. In one open-label evaluation (n = 9) the mean dose during the first 6 to 8 weeks was 34.4 mg/day PO, with a range of 20 to 60 mg/day PO. The median time to attain improvement ("much to very much improved") was 7.5 weeks. A benzodiazepine was used in 67% of the patients while awaiting the clinical response to the SSRI.

For the treatment of generalized anxiety disorder (GAD)*:
Oral dosage:
Children and Adolescents 7 to 17 years: 10 mg PO once daily for 1 week, then 20 mg PO once daily. In a randomized controlled trial of pediatric patients 7 years of age and older with a diagnosis of 1 or more anxiety disorders including GAD, fluoxetine-treated patients with GAD had a significantly better clinical response than placebo-treated patients (67% vs. 36%). Initial improvement seen at 4 weeks; improvement was sustained during the 1-year, open-label, follow-up study.

For the treatment of social phobia (social anxiety disorder)*:
Oral dosage:
Children and Adolescents 7 to 17 years: 10 mg/day PO initially, followed by titration; a target dose of 20 mg to 40 mg/day PO may be effective for treating social phobia in children and adolescents. In one randomized, placebo-controlled trial comparing the effectiveness of fluoxetine to Social Effectiveness Therapy for Children (SET-C) in pediatric patients with a primary diagnosis of social phobia, fluoxetine was titrated as follows: 10 mg/day PO for 2 weeks, 20 mg/day for 2 weeks, 30 mg/day for 2 weeks, and 40 mg/day thereafter unless side effects necessitated a dose reduction. At study end, both SET-C and fluoxetine decreased social distress equally; however, SET-C was superior to fluoxetine in the percentage of treatment responders (100% vs. 61%), lack of post-treatment diagnosis (53% vs. 21.2%), and achievement of high end-state functioning (94% vs. 55.6%). SET-C was the only treatment superior to placebo in improving social skills, decreasing anxiety in specific social interactions, and enhancing social competence. In a separate study assessing fluoxetine treatment in various childhood anxiety disorders, 76% of patients with primary social phobia were assessed as much or very much improved compared to 21% of patients treated with placebo. In one study of 60 patients aged 15 to 77 years, the findings were less robust, and fluoxetine failed to show a significant difference from placebo.

For the treatment of bulimia nervosa*:
Oral dosage (regular capsules, tablets, or oral solution):
Children and Adolescents 12 to 17 years: 20 mg PO once daily, initially. Increase the dose by 20 mg/day every 3 days to a maximum dose of 60 mg/day. In a small study of 10 adolescents with a diagnosis of bulimia nervosa or eating disorder not otherwise specified, fluoxetine was associated with a significant decrease in the core behavioral symptoms of bulimia nervosa (e.g., binging, purging) and was used with supportive psychotherapy. Clinical practice guidelines highlight that fluoxetine has also been well-studied in the adolescent population for the treatment of depression and anxiety, which are often reported as concomitant conditions in patients with bulimia nervosa.

For the treatment of autistic disorder*:
Oral dosage (regular capsules, tablets or oral solution):
Children and Adolescents 2 to 17 years: 2.5 mg/day PO initially, titrated based on weight and tolerability to a maximum target dose of 0.8 mg/kg/day PO in older children and adolescents by week 4. Weight-based dosing of 0.15 to 0.5 mg/kg/day has also been used in younger children. One 8-week controlled trial of children (5 years and older) and adolescents (n = 45 total) indicated that fluoxetine treatment was associated with a significant reduction in repetitive behaviors. In a long-term study (duration: 5 to 76 months) of children 2 to 8 years (n = 129), 17% of patients had an excellent response, 52% a good response, 8% fair, and 23% poor. Forty percent of good/excellent responders had optimal daily doses more than 12 mg/day (with weight-based dosing not exceeding 40 mg/day PO). Improvement with fluoxetine had a strong correlation with familial major affective disorders. Behavioral hyperactivity may limit treatment in some patients.

For the treatment of separation anxiety disorder*:
Oral dosage (regular capsules, tablets or oral solution):
Children 9 to 12 years: 5 mg/day PO initially, with titration to effective doses. Children (n = 5) were titrated from an initial dose of 5 mg/day up to 20 mg/day in week 4, with subsequent increases to a maximum of 40 mg/day if clinically indicated. The mean daily dose for children was 24 mg/day. In this open-label study of 16 pediatric patients with one or more anxiety disorders, 10 out of 10 patients with separation anxiety disorder showed clinical improvement (4 rated as improved and 6 rated as much improved); the patients improved over 6 to 9 weeks (mean of 5 weeks). Youth with only 1 diagnosis responded to lower doses than those with 2 or more diagnoses. After treatment with fluoxetine, 7 of 10 patients with separation anxiety disorder no longer met diagnosis criteria. However, in a separate study of mixed anxiety disorders, clinical response to fluoxetine was similar to placebo, although patients with SCARED-C (Screen for Child Anxiety Related Emotional Disorders, child version) scores of at least 30 at intake showed a trend toward better response to fluoxetine than placebo. Further study is needed to evaluate the safety and efficacy of SSRIs in treating separation anxiety disorder.
Adolescents: 5 mg/day PO initially, with titration to effective doses. Adolescents (n = 11) were titrated from an initial dose of 5 mg/day up to 20 mg/day in week 3, with subsequent increases to a maximum of 80 mg/day if clinically indicated. The mean daily dose for adolescents was 40 mg/day. In this open-label study of 16 pediatric patients with one or more anxiety disorders, 10 out of 10 patients with separation anxiety disorder showed clinical improvement (4 rated as improved and 6 rated as much improved); the patients improved over 6 to 9 weeks (mean of 5 weeks). Youth with only 1 diagnosis responded to lower doses than those with 2 or more diagnoses. After treatment with fluoxetine, 7 of 10 patients with separation anxiety disorder no longer met diagnosis criteria. However, in a separate study of mixed anxiety disorders, clinical response to fluoxetine was similar to placebo, although patients with SCARED-C (Screen for Child Anxiety Related Emotional Disorders, child version) scores of at least 30 at intake showed a trend toward better response to fluoxetine than placebo. Further study is needed to evaluate the safety and efficacy of SSRIs in treating separation anxiety disorder.

For the treatment of selective mutism* in children who have failed an adequate trial of psychotherapy:
Oral dosage (regular capsules, tablets and oral solution):
Children and Adolescents 4 to 17 years: Pharmacotherapy for selective mutism is not well-studied. Various dosage titrations have been used. Target doses range from 8 mg/day PO to 60 mg/day PO; lower weight children usually receive lower target doses. Weight based dosing of 0.3 mg/kg/day PO up to 0.6 mg/kg/day PO has also been used. The majority of data use an initial dose of 20 mg/day with gradual titration; Max: 60 mg/day PO. One case report documented an initial dose of 4 mg/day PO and a final dose of 8 mg/day in a 4-year-old child, with some improvement noted within 5 days. In another study, the mean dose at study end was 28.1 mg/day (range: 10 mg to 60 mg/day). Significant improvement may not occur for 6 to 12 weeks, and individual response is variable. The most frequently reported adverse effects include excitement or behavioral disinhibition, insomnia, jitteriness, and headache. Further study is needed to evaluate safety and efficacy.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 year: Safety and efficacy have not been established.
2 to 3 years: Safety and efficacy have not been established. Doses up to 0.5 mg/kg/day PO (Max: 40 mg/day) have been used off-label in children with autism. Do not use the once-weekly dosage form.
4 to 6 years: Safety and efficacy have not been established. Doses up to 0.6 mg/kg/day PO (Max: 60 mg/day) have been used off-label in children with selective mutism. Do not use the once-weekly dosage form.
7 to 12 years: 60 mg/day PO. Do not use the once-weekly dosage form.
-Adolescents
60 mg/day PO. Safety and efficacy not established for the once-weekly dosage form.

Patients with Hepatic Impairment Dosing
A lower or less frequent dose should be used in patients with liver disease; however, quantitative guidelines are not available.

Patients with Renal Impairment Dosing
CrCl less than 10 mL/minute: Higher concentrations of the metabolites of fluoxetine (e.g., norfluoxetine) may be present in patients with severe renal impairment; however, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

Intermittent hemodialysis
In a study of adult patients on hemodialysis, the steady-state plasma concentrations of fluoxetine and its active metabolite norfluoxetine were comparable to those of patients with normal renal function during use of dosages of 20 mg/day PO for 2 months; there are no routine dosage adjustments recommended for patients receiving dialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The precise antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression and anxiety disorders is not fully understood, but involves selective serotonin reuptake blockade at the neuronal membrane, which enhances the actions of serotonin (5-HT). Initially, SSRIs increase availability of serotonin in the somatodendritic area through serotonin reuptake blockade at the serotonin transport pump. During long-term administration of SSRIs, serotonin autoreceptors are down-regulated and desensitized, allowing the neuron to increase serotonin release in the axon terminal synapses and increase its neuronal impulses. Because of the delay in therapeutic response to SSRIs, it is theorized that the change in the balance of serotonin receptors over time is an important mechanism of effect. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do tricyclic antidepressants due to dramatically decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors. Norfluoxetine, the active metabolite of fluoxetine, is a potent and selective reuptake inhibitor of serotonin with activity which is essentially bioequivalent to the parent compound.

Pharmacokinetics: Fluoxetine is administered orally. Steady-state plasma concentrations of fluoxetine and its principal active metabolite norfluoxetine are achieved after 3 to 4 weeks of daily dosing. Both fluoxetine and the active metabolite, norfluoxetine, exist as enantiomers. In vitro, each enantiomer, except R-norfluoxetine appears to have equivalent potency in the inhibition of serotonin reuptake. However, these four compounds differ in kinetics and no relationship between serum concentrations and clinical effect has been defined. Fluoxetine is highly protein-bound (94.5%) predominantly to alpha-1 acid glycoprotein. The drug is well distributed, and it readily crosses the blood-brain barrier. Fluoxetine is demethylated in the liver to several metabolites. The only known active metabolite is norfluoxetine, which appears to be as effective as its parent in the blockade of serotonin reuptake. Fluoxetine is primarily a substrate for CYP2D6; however, both CYP2D6 and CYP2C9 contribute to the formation of R-norfluoxetine, whereas only CYP2D6 is responsible for conversion to S-norfluoxetine. The pharmacokinetic properties and relative proportion of fluoxetine and metabolites may be altered in poor CYP2D6 metabolizers. When compared with normal metabolizers, the total sum at steady-state of the plasma concentrations of the 4 active enantiomers is not significantly greater among poor metabolizers. Fluoxetine has the slowest elimination of the SSRIs. The elimination half-life after chronic fluoxetine administration is 4 to 6 days; however, there is considerable individual variation, which may be associated with variance in the rates of N-demethylation and hydroxylation. In one pharmacokinetic evaluation, the mean terminal half-life of norfluoxetine after a single dose was 8.6 days and after multiple dosing was 9.3 days. The primary route of elimination appears to be metabolism in the liver to metabolites that are subsequently excreted by the kidneys.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP2C19, CYP3A4, CYP2C9
Fluoxetine is a primary substrate of CYP2D6. Fluoxetine is a potent inhibitor of CYP2D6 and CYP2C19 and a weak inhibitor of CYP3A4 and CYP2C9. The inhibition of CYP3A4 by fluoxetine is likely not clinically significant; however, some data suggest that norfluoxetine is a moderate inhibitor of CYP3A4, and the possibility of clinically relevant drug interactions with CYP3A4 substrates cannot be excluded.


-Route-Specific Pharmacokinetics
Oral Route
Fluoxetine is well absorbed from the GI tract after oral administration. The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. Peak plasma concentrations are observed in 6 to 8 hours. The extent of absorption is not affected by food; therefore, the drug may be administered without regard to meals.


-Special Populations
Pediatrics
Children and Adolescents
Evaluations in pediatric patients have shown that the average steady-state fluoxetine concentrations in children 6 to 12 years are approximately 2-fold higher than adolescents 13 to 18 years, and the average norfluoxetine concentrations are about 1.5-fold higher in children than adolescents. These differences are primarily attributable to differences in weight between the groups, with lower weight children having higher plasma concentrations than adolescents. Although higher average steady-state concentrations of fluoxetine and norfluoxetine have been observed in children than adults, the concentrations are within the range observed in the adult population.

Hepatic Impairment
Hepatic impairment can affect the elimination of fluoxetine. The half-life of fluoxetine and norfluoxetine are prolonged to 7.6 days and 12 days, respectively, in patients with cirrhosis versus healthy controls.

Renal Impairment
Drug accumulation has not been observed in patients receiving dialysis. Although higher concentrations of the renally excreted metabolites of fluoxetine are possible in patients with severe renal impairment (e.g., renal failure), use of a lower or less frequent dose is generally not necessary in renally impaired patients.