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WARNING: Suicidality and Antidepressant Drugs:
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluoxetine capsules or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluoxetine is not approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD). (See WARNINGS, PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use.)
Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration; fluoxetine was initially developed and marketed as an antidepressant (Prozac®*, fluoxetine capsules, USP). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the molecular formula of C17H18F3NO•HCl. Its molecular weight is 345.79. The structural formula is:
Fluoxetine hydrochloride, USP is a white to off-white crystalline powder with a solubility of 14 mg/mL in water.
Each capsule contains fluoxetine hydrochloride, USP equivalent to 10 mg (32.3 µmol) or 20 mg (64.7 µmol) of fluoxetine. The capsules also contain: colloidal silicon dioxide, magnesium stearate, pregelatinized starch (corn) and sodium lauryl sulfate. In addition, each of the empty gelatin capsules contain the following:
10 mg—FD&C Blue No. 1, FD&C Green No. 3, FD&C Yellow No. 6, gelatin, and titanium dioxide
20 mg—FD&C Red No. 40, gelatin, and titanium dioxide.
The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
The mechanism of action of fluoxetine in premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in humans 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 α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of certain psychoactive drugs. Fluoxetine has little affinity for these receptors.
Absorption, Distribution, Metabolism, and Excretion
Systemic Bioavailability
In humans, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours.
Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food.
Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS).
Enantiomers
Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady-state.
Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.
Clinical Issues Related To Metabolism/Elimination
The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use.
Variability in Metabolism
A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady-state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady-state of the plasma concentrations of the four active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit.
Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see PRECAUTIONS: Drug Interactions).
Accumulation and Slow Elimination
The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady-state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.
The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). 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 capsules.
As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS: Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION).
In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see PRECAUTIONS: Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD)
The effectiveness of fluoxetine hydrochloride for the treatment of PMDD was established in three placebo-controlled trials (one intermittent and two continuous dosing). In an intermittent dosing trial described below, patients met Diagnostic and Statistical Manual-4th edition (DSM-IV) criteria for PMDD. In the continuous dosing trials described below, patients met Diagnostic and Statistical Manual-3rd edition revised (DSM-IIIR) criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as PMDD in the DSM-IV. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of fluoxetine in combination with oral contraceptives for the treatment of PMDD is unknown.
In an intermittent dosing double-blind, parallel group study of 3 months duration, patients (N = 260 randomized) were treated with fluoxetine 10 mg/day, fluoxetine 20 mg/day, or placebo. Fluoxetine or placebo was started 14 days prior to the anticipated onset of menstruation and was continued through the first full day of menses. Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Fluoxetine 20 mg/day was shown to be significantly more effective than placebo as measured by the DRSP total score. Fluoxetine 10 mg/day was not shown to be significantly more effective than placebo on this outcome. The average DRSP total score decreased 38% on fluoxetine 20 mg/day, 35% on fluoxetine 10 mg/day, and 30% on placebo.
In the first continuous dosing double-blind, parallel group study of 6 months duration involving N = 320 patients, fixed doses of fluoxetine 20 and 60 mg/day given daily throughout the menstrual cycle were shown to be significantly more effective than placebo as measured by a Visual Analogue Scale (VAS) total score (including mood and physical symptoms). The average total VAS score decreased 7% on placebo treatment, 36% on 20 mg, and 39% on 60 mg fluoxetine. The difference between the 20 mg and 60 mg doses was not statistically significant. The following table shows the percentage of patients meeting criteria for either moderate or marked improvement on the VAS total score:
Percentage of Patients Moderately and Markedly Improved (> 50% and 75% reduction, respectively, from baseline Luteal Phase VAS total score)
Fluoxetine 20 mg
In a second continuous dosing double-blind, cross-over study, patients (N = 19) were treated with fluoxetine 20 to 60 mg/day (mean dose = 27 mg/day) and placebo daily throughout the menstrual cycle for a period of 3 months each. Fluoxetine was significantly more effective than placebo as measured by within cycle follicular to luteal phase changes in the VAS total score (mood, physical, and social impairment symptoms). The average VAS total score (follicular to luteal phase increase) was 3.8 times higher during placebo treatment than what was observed during fluoxetine treatment.
In another continuous dosing double-blind, parallel group study, patients with LLPDD (N = 42) were treated daily with fluoxetine 20 mg/day, bupropion 300 mg/day, or placebo for 2 months. Neither fluoxetine nor bupropion was shown to be superior to placebo on the primary endpoint, i.e., response rate [defined as a rating of 1 (very much improved) or 2 (much improved) on the CGI], possibly due to sample size.
Fluoxetine capsules, USP are indicated for the treatment of premenstrual dysphoric disorder (PMDD). The efficacy of fluoxetine in the treatment of PMDD was established in three placebo-controlled trials (see CLINICAL TRIALS).
The essential features of PMDD, according to the DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.
The effectiveness of fluoxetine capsules in long-term use, that is, for more than 6 months, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use fluoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Fluoxetine capsules are contraindicated in patients known to be hypersensitive to it.
Monoamine Oxidase Inhibitors
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 WARNINGS and DOSAGE AND ADMINISTRATION).
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 WARNINGS and DOSAGE AND ADMINISTRATION).
Pimozide
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Thioridazine
Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see WARNINGS).
Clinical Worsening and Suicide Risk
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 nine 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 vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
Drug-Placebo Difference in
Number of Cases of Suicidality
Per 1,000 Patients Treated
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.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION: Discontinuation of Treatment with Fluoxetine, for a description of the risks of discontinuation of fluoxetine).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for fluoxetine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
It should be noted that fluoxetine is not approved for use in treating any indications in the pediatric population.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that fluoxetine is not approved for use in treating bipolar depression.
Serotonin Syndrome
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, 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.
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 and DOSAGE AND ADMINISTRATION).
If concomitant use of fluoxetine with other serotonergic drugs including, 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.
Rash and Possibly Allergic Events
In four clinical trials for PMDD, 4% of 415 patients treated with fluoxetine reported rash and/or urticaria. None of these cases were classified as serious and 2 of 415 patients (both receiving 60 mg) were withdrawn from treatment because of rash and/or urticaria.
In U.S. fluoxetine clinical trials for conditions other than PMDD, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely.
In premarketing clinical trials of fluoxetine for conditions other than PMDD, two patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of fluoxetine for other indications, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events.
Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.
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.
Potential Interaction with Thioridazine
In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine (see PRECAUTIONS).
Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as Torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism (see CONTRAINDICATIONS).
SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation (see Drug Interactions).
Anxiety and Insomnia
In two placebo-controlled trials of fluoxetine in PMDD, treatment-emergent adverse events were assessed. Rates were as follows for fluoxetine 20 mg (the recommended dose) continuous and intermittent pooled, fluoxetine 60 mg continuous, and pooled placebo, respectively: anxiety (3%, 9%, and 4%); nervousness (5%, 9%, and 3%); and insomnia (9%, 26%, and 7%). For individual rates for fluoxetine 20 mg given as continuous and intermittent dosing, see Table 2 and accompanying footnote under ADVERSE REACTIONS. Events associated with discontinuation for fluoxetine 20 mg continuous and intermittent pooled, fluoxetine 60 mg continuous, and pooled placebo, respectively, were: anxiety (0%, 6%, and 1%); nervousness (1%, 0%, and 0.5%); and insomnia (1%, 4%, and 0.5%). In U.S. placebo-controlled clinical trials of fluoxetine for other approved indications, anxiety, nervousness, and insomnia have been among the most commonly reported adverse events (see ADVERSE REACTIONS: Table 3).
Altered Appetite and Weight
In two placebo-controlled trials of fluoxetine in PMDD, rates for anorexia were as follows for fluoxetine 20 mg (the recommended dose) continuous and intermittent pooled, fluoxetine 60 mg continuous, and pooled placebo, respectively: 4%, 13%, and 2%. For individual rates for fluoxetine 20 mg continuous and intermittent, see footnote accompanying Table 2 under ADVERSE REACTIONS. In two placebo-controlled trials (only one of which included a dose of 60 mg/day), potentially clinically significant weight gain (≥ 7%) occurred in 8% of patients on fluoxetine 20 mg, 6% of patients on fluoxetine 60 mg, and 1% of patients on placebo. Potentially clinically significant weight loss (≥ 7%) occurred in 7% of patients on fluoxetine 20 mg, 12% of patients on fluoxetine 60 mg, and 3% of patients on placebo. In U.S. placebo-controlled clinical trials of fluoxetine for other approved indications, changes in appetite and weight have also been reported (see ADVERSE REACTIONS: Table 3 and Other Events Observed in U.S. Clinical Trials).
Activation of Mania/Hypomania
No patients treated with fluoxetine in four PMDD clinical trials (N = 415) reported mania/hypomania. In all U.S. fluoxetine clinical trials for conditions other than PMDD, 0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may occur with medications used to treat depression, especially in patients predisposed to Bipolar Affective Disorder.
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, 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 SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. 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.
No patients treated with fluoxetine in four PMDD clinical trials (N = 415) reported seizures. In all U.S. fluoxetine clinical trials for conditions other than PMDD, 0.2% of 10,782 patients reported seizures. Antidepressant medication should be introduced with care in patients with a history of seizures.
The Long Elimination Half-Lives of Fluoxetine and its Metabolites
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 (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Use in Patients with Concomitant Illness
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 for a condition other than PMDD were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.
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 (see CLINICAL PHARMACOLOGY: Liver Disease). A lower or less frequent dose should be used in patients with cirrhosis (see DOSAGE AND ADMINISTRATION).
Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma (see CLINICAL PHARMACOLOGY: Renal Disease). Use of a lower or less frequent dose for renally impaired patients is not routinely necessary (see DOSAGE AND ADMINISTRATION).
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.
Discontinuation of Treatment with Fluoxetine
During marketing of fluoxetine and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events 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 events are generally self limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug (see DOSAGE AND ADMINISTRATION).
Interference with Cognitive and Motor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illnesses and Suicidal Thoughts or Actions" is available for fluoxetine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine.
Patients should be advised that taking fluoxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding (see PRECAUTIONS: General: Abnormal Bleeding).
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and triptans, tramadol or other serotonergic agents.
There are no specific laboratory tests recommended.
As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY: Accumulation and Slow Elimination).
Drugs Metabolized by CYP2D6
Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS).
Drugs Metabolized by CYP3A4
In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
CNS Active Drugs
The risk of using fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (see CLINICAL PHARMACOLOGY: Accumulation and Slow Elimination).
Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.
Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated (see CONTRAINDICATIONS). For thioridazine, see CONTRAINDICATIONS and WARNINGS.
The half-life of concurrently administered diazepam may be prolonged in some patients (see CLINICAL PHARMACOLOGY: Accumulation and Slow Elimination). Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.
There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.
Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.
Monoamine Oxidase Inhibitors (MAOIs)
See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.
In two studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued (see CLINICAL PHARMACOLOGY: Accumulation and Slow Elimination, and Drug Interactions: Drugs Metabolized by CYP2D6).
Serotonergic Drugs
Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine, and the potential for serotonin syndrome, caution is advised when fluoxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John's Wort (see WARNINGS: Serotonin Syndrome).
Triptans
There have been rare post-marketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluoxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome).
Potential Effects of Coadministration of Drugs Tightly Bound to Plasma Proteins
Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs (see CLINICAL PHARMACOLOGY: Accumulation and Slow Elimination).
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued.
Electroconvulsive Therapy (ECT)
There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) was not observed.
The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis], produced no evidence of carcinogenicity.
Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.
Impairment of Fertility
Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use).
In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/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 on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD 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 (0.6 times the MRHD on a mg/m2 basis). Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association.
There have also been postmarketing reports of premature births in pregnant women exposed to fluoxetine or other SSRIs.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION).
Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need.
In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m2 basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.
The diagnosis of PMDD is not applicable to postmenopausal women.
In one of three placebo-controlled, continuous-dosing trials and one placebo-controlled, intermittent-dosing trial of fluoxetine in PMDD, treatment-emergent adverse events reporting rates were assessed. The information from Table 2 included under ADVERSE REACTIONS is based on data from the continuous-dosing trial at the recommended dose of fluoxetine (fluoxetine 20 mg, N = 104; placebo, N = 108) and data from the intermittent-dosing trial of fluoxetine in PMDD (fluoxetine 20 mg, N = 86; placebo, N = 88). In addition, a broader set of information on treatment-emergent adverse events in the population of female patients, 18 to 45 years of age from the U.S. placebo-controlled depression, OCD, and bulimia clinical trials, is presented for comparison (see Table 3).
Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories.
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.
Incidence in Placebo-Controlled PMDD Clinical Trials: Table 2 enumerates the most common treatment-emergent adverse events associated with the use of fluoxetine 20 mg (incidence of at least 5% for fluoxetine 20 mg and greater than placebo) for the treatment of PMDD.
Table 2: Most Common Treatment-Emergent Adverse Events: Incidence in PMDD Placebo-Controlled Clinical Trials
Included in the table are events reported by at least 5% of patients taking fluoxetine 20 mg either continuously or intermittently. For additional adverse event terms referenced in PRECAUTIONS, reporting rates for fluoxetine 20 mg continuous and intermittent were, respectively: anxiety 4.8%, 1.2% and anorexia 3.8%, 3.5%.
Thinking abnormal is the COSTART term that captures concentration difficulties.
Body System/
Adverse Event*
20 mg/day Continuously
20 mg/day Intermittently
(N = 86)
Placebo (Pooled)
Thinking abnormal†
Incidence in U.S. Depression, OCD, and Bulimia Placebo-Controlled Clinical Trials (Excluding Data from Extensions of Trials): Table 3 enumerates the most common treatment-emergent adverse events associated with the use of fluoxetine up to 80 mg (incidence of at least 2% for fluoxetine and greater than placebo) in female patients ages 18 to 45 years from U.S. placebo-controlled clinical trials in the treatment of depression, OCD, and bulimia.
Table 3: Treatment-Emergent Adverse Events: Incidence in Female Patients Ages 18 to 45 Years in U.S. Depression, OCD, and Bulimia Placebo-Controlled Clinical Trials
Included are events reported by at least 2% of patients taking fluoxetine, except the following events, which had an incidence on placebo > fluoxetine (depression, OCD, and bulimia combined): back pain, cough increased, depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection, myalgia, pain, pruritus, rhinitis, sinusitis.
(N = 1,145)
Metabolic and Nutritional Disorders
Abnormal dreams
-- Incidence less than 0.5%.
Associated with Discontinuation in Two Placebo-Controlled PMDD Clinical Trials: In a continuous-dosing PMDD placebo-controlled trial, the most common adverse event (incidence at least 2% for fluoxetine 20 mg and greater than placebo) associated with discontinuation was nausea (3% for fluoxetine 20 mg, N = 104 and 1% for placebo, N = 108). In an intermittent-dosing placebo-controlled trial, no events associated with discontinuation reached an incidence of 2% for fluoxetine 20 mg. In these clinical trials, more than one event may have been recorded as the cause of discontinuation.
Associated with Discontinuation in U.S. Depression, OCD, and Bulimia Placebo-Controlled Clinical Trials (Excluding Data from Extensions of Trials): In female patients age 18 to 45 years in U.S. depression, OCD, and bulimia placebo-controlled clinical trials combined, which collected a single primary event associated with discontinuation (incidence at least 1% for fluoxetine and at least twice that for placebo), insomnia (1%, N = 561) was the only event reported.
Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a mood-related disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. For example, in women (age 18 to 45) receiving fluoxetine for indications other than PMDD, decreased libido was seen at an incidence of 4% for fluoxetine compared with 1% for placebo. There have been spontaneous reports in women (age 18 to 45) taking fluoxetine for indications other than PMDD of orgasmic dysfunction, including anorgasmia.
There are no adequate and well controlled studies examining sexual dysfunction with fluoxetine treatment.
Other Events Observed in U.S. Clinical Trials
Following is a list of all treatment-emergent adverse events reported at anytime by females and males taking fluoxetine in all U.S. clinical trials for conditions other than PMDD as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 2 or 3 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to fluoxetine use was considered remote; (4) events occurring in only one patient treated with fluoxetine and which did not have a substantial probability of being acutely life threatening; and (5) events that could only occur in males.
Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Body as a Whole: Frequent: chest pain and chills; Infrequent: chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction.
Cardiovascular System: Frequent: hemorrhage, hypertension; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.
Digestive System: Frequent: increased appetite, nausea and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.
Endocrine System: Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus.
Hemic and Lymphatic System: Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia.
Metabolic and Nutritional: Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased.
Musculoskeletal System: Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.
Nervous System: Frequent: agitation, amnesia, confusion, emotional lability, paresthesia, and sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder1, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor.
Respiratory System: Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.
Skin and Appendages: Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.
Special Senses: Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.
Urogenital System: Infrequent: abortion2, albuminuria, amenorrhea2, anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation2, fibrocystic breast2, hematuria, leukorrhea2, menorrhagia2, metrorrhagia2, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage2; Rare: breast engorgement, glycosuria, hypomenorrhea2, kidney pain, oliguria, uterine hemorrhage2, uterine fibroids enlarged2.
1 Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.
2 Adjusted for gender.
Postintroduction Reports
Voluntary reports of adverse events temporally associated with fluoxetine that have been received since market introduction of fluoxetine and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77 year old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of pre-existing movement disorders, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson Syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including Torsades de pointes-type arrhythmias), and violent behaviors.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Fluoxetine is not a controlled substance.
Physical and Psychological Dependence
Human Experience
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 nonfatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.
Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, one patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9 year old boy who had a history of OCD, Tourette's syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all six overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was non-lethal.
Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including Torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope.
Animal Experience
Among six dogs purposely overdosed with oral fluoxetine, five experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically.
In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose (see Management of Overdose).
Management of Overdose
Treatment should consist of those general measures employed in the management of overdosage with any SSRI.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
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 PRECAUTIONS).
The recommended dose of fluoxetine capsules for the treatment of PMDD is 20 mg/day given continuously (every day of the menstrual cycle) or intermittently (defined as starting a daily dose 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeating with each new cycle). The dosing regimen should be determined by the physician based on individual patient characteristics. In a study comparing continuous dosing of fluoxetine capsules 20 and 60 mg/day to placebo, both doses were proven to be effective, but there was no statistically significant added benefit for the 60 mg/day compared with the 20 mg/day dose. Fluoxetine capsule doses above 60 mg/day have not been systematically studied in patients with PMDD. The maximum fluoxetine capsule dose should not exceed 80 mg/day.
As with many other medications, a lower or less frequent dosage should be considered in patients with hepatic impairment. A lower or less frequent dosage should also be considered for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary (see CLINICAL PHARMACOLOGY: Liver Disease and Renal Disease, and PRECAUTIONS: Use in Patients with Concomitant Illness).
Maintenance/Continuation Treatment
Systematic evaluation of fluoxetine capsules has shown that its efficacy in PMDD is maintained for periods of up to 6 months at a dose of 20 mg/day given continuously and up to 3 months at a dose of 20 mg/day given intermittently, (see CLINICAL TRIALS). Patients should be periodically reassessed to determine the need for continued treatment.
Treatment of Pregnant Women During the Third Trimester
Neonates exposed to fluoxetine and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with fluoxetine capsules during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering fluoxetine capsules in the third trimester.
Discontinuation of Treatment with Fluoxetine Capsules
Symptoms associated with discontinuation of fluoxetine capsules and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
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).
Use of Fluoxetine with Other MAOIs, Such as Linezolid or Methylene Blue
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).
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 2 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).
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 clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Fluoxetine Capsules, USP are available containing fluoxetine hydrochloride, USP equivalent to 10 mg or 20 mg of fluoxetine.
The 10 mg capsule is a hard-shell gelatin capsule with a blue green opaque cap and a blue green opaque body axially printed with MYLAN over 5410 in black ink on both the cap and the body. The capsule is filled with white to off-white powder. They are available as follows:
bottles of 28 capsules
The 20 mg capsule is a hard-shell gelatin capsule with a red opaque cap and a red opaque body axially printed with MYLAN over 5420 in black ink on both the cap and the body. The capsule is filled with white to off-white powder. They are available as follows:
PHARMACIST: Dispense a Medication Guide with each prescription.
ANIMAL TOXICOLOGY
FLUOXETINE CAPSULES, USP
(floo oxʹ e teen)
10 mg and 20 mg
Read the Medication Guide that comes with fluoxetine capsules 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 you want to learn more about.
Fluoxetine capsules are in a class of drugs called selective serotonin reuptake inhibitors (SSRIs), which are often used for the treatment of depression and anxiety disorders. Although fluoxetine capsules are not a treatment for depression, it contains fluoxetine hydrochloride, the same active ingredient in some antidepressants.
What is the most important information I should know about fluoxetine capsules?
Fluoxetine capsules and other antidepressant medicines may cause serious side effects including:
1. Suicidal thoughts or actions:
Fluoxetine capsules 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 capsules are 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:
acting aggressive or violent
new or worse anxiety or panic attacks
feeling agitated, restless, angry or irritable
an increase in activity or talking more than what is normal for you
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine capsules 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
3. Severe allergic reactions:
swelling of the face, tongue, eyes or mouth
rash, itchy welts (hives) or blisters, alone or with fever or joint pain
4. 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
5. Seizures or convulsions
6. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.
7. Abnormal bleeding: Fluoxetine capsules 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 (NSAID's, like ibuprofen or naproxen), or aspirin.
8. Visual Problems
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.
9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:
weakness or feeling unsteady
confusion, problems concentrating or thinking or memory problems
Do not stop fluoxetine capsules without first talking to your healthcare provider. Stopping fluoxetine capsules 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
What are fluoxetine capsules?
Fluoxetine capsules are a prescription medicine used to treat premenstrual dysphoric disorder (PMDD).
It is not known if fluoxetine capsules are safe and effective in children.
Talk with your healthcare provider if you do not think that your condition is getting better with fluoxetine capsules treatment.
Who should not take fluoxetine capsules?
Do not take fluoxetine capsules if you:
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 capsules unless directed to do so by your healthcare provider.
Do not start fluoxetine capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.
Women who take fluoxetine capsules 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:
uncontrolled muscle spasms
stiff muscles
rapid changes in heart rate or blood pressure
loss of consciousness (pass out)
take Mellaril®* (thioridazine). Do not take Mellaril®* within 5 weeks of stopping fluoxetine capsules 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 capsules?
Ask if you are not sure.
Before starting fluoxetine capsules, 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
Tramadol and fentanyl
Over-the-counter supplements such as tryptophan or St. John's Wort
have liver 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 or had bleeding problems
are pregnant or plan to become pregnant. It is not known if fluoxetine capsules will harm your unborn baby.
are breastfeeding or plan to breastfeed. Some fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine capsules.
Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fluoxetine capsules 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 capsules with your other medicines. Do not start or stop any medicine while taking fluoxetine capsules without talking to your healthcare provider first.
If you take fluoxetine capsules, you should not take any other medicines that contain fluoxetine hydrochloride:
Symbyax®*
Prozac®*
Prozac®*Weekly™
How should I take fluoxetine capsules?
Take fluoxetine capsules exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine until it is the right dose for you.
Talk to your healthcare provider if your symptoms do not get better.
Fluoxetine capsules may be taken with or without food.
If you take too much fluoxetine, call your healthcare provider or go to the nearest hospital emergency room right away.
What should I avoid while taking fluoxetine capsules?
Fluoxetine capsules 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 capsules affects you. Do not drink alcohol while using fluoxetine capsules.
What are the possible side effects of fluoxetine capsules?
Fluoxetine capsules may cause serious side effects, including:
See "What is the most important information I should know about fluoxetine capsules?"
Problems with blood sugar control. Women who have diabetes and take fluoxetine capsules may have problems with low blood sugar while taking fluoxetine capsules. High blood sugar can happen when fluoxetine capsules are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine capsules.
Feeling anxious or trouble sleeping
The most common side effects of fluoxetine capsules include:
weakness (asthenia)
feeling anxious or nervous
thinking differently
flu symptoms
runny or stuffy nose (rhinitis)
sore throat (pharyngitis)
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 capsules. For more information, ask your healthcare provider or pharmacist.
How should I store fluoxetine capsules?
Keep fluoxetine capsules and all medicines out of the reach of children.
General information about fluoxetine capsules
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine capsules for a condition for which it was not prescribed. Do not give fluoxetine capsules to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about fluoxetine capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine capsules that is written for healthcare professionals. For more information about fluoxetine capsules call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).
What are the ingredients in fluoxetine capsules?
Active ingredient: fluoxetine hydrochloride, USP
Inactive ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch (corn), and sodium lauryl sulfate. In addition, each of the empty gelatin capsules contain the following:
10 mg - FD&C Blue No. 1, FD&C Green No. 3, FD&C Yellow No. 6, gelatin, and titanium dioxide
20 mg - FD&C Red No. 40, gelatin, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
*The brands listed are trademarks of their respective owners.
FLUXPD:R7
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
Rx only 28 Capsules
Each capsule contains fluoxetine
hydrochloride, USP equivalent to
10 mg of fluoxetine.
[See USP Controlled Room
RM5410BD4
MAGNESIUM STEARATE (UNII: 70097M6I30)
FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S)
FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
Color BLUE (blue green opaque) Score no score
Flavor Imprint Code MYLAN;5410
NDC:0378-5410-28 28 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 11/17/2008 10/31/2019
Color RED (red opaque) Score no score
Document Id: 78bdcdf7-4ad8-4481-a5eb-52654bfda6dc
Set id: c06f80cf-be99-0b77-ebd7-7a5f1561d4b4


WASHINGTON, July 25, 2018 (GLOBE NEWSWIRE) -- FTI Consulting, Inc. (NYSE:FCN) has found slightly higher year-over-year pay increases in 2017 REIT executive compensation levels despite lower one-year total shareholder returns ("TSR") in the REIT industry. These key findings were revealed in the FTI Consulting 2017-2018 REIT Executive Compensation Trends study, which focuses on the pay practices at publicly traded REITs.
According to the study, REIT executive compensation increased 7% in 2017 compared to 5% in 2016. Conducted by the Real Estate & Infrastructure industry group at FTI Consulting, the study details year-over-year compensation changes and provides meaningful insight into recent REIT compensation market trends.
In 2018, 15 self-managed REITs received "against" say-on-pay voting recommendations, up 4% from the prior year. According to the study, ISS continues to be critical of goal setting for incentive programs by citing the rigor of performance goals as a concern at 67% of REITs with a negative ISS say-on-pay voting recommendation. "REITs will need to consider not only the appropriateness of the performance metrics in their incentive plans, but also the rigor of the goals," Ms. Gaynor said. From 2016 to 2017, the median actual annual incentive payout as a percent of target declined year-over-year from 129% to 123%.
The percentage of REITs now using performance-based equity seems to have stabilized in the past couple years, with 83% of REITs using such programs. In 2017, 26% of REITs included a payout modifier to their performance share plan that adjust the payout based on a secondary measure, which is typically a TSR metric. "Performance share modifiers are expected to become more prevalent given the focus on payouts above target in situations when absolute TSR is negative," Mr. Portal added.
The 2017-2018 REIT Executive Compensation Trends study also showed that compensation trends by position varied widely: total compensation remained unchanged at 0.1% among chairpersons, while it increased 10.3% among chief financial officers, the highest increase among the seven executive categories studied and significantly higher than last year's highest median increase of 7.4%. The study tracked compensation changes across 566 incumbents in the following positions: chairman (+0.1%), chief executive officer (+6.0%), chief operating officer (+7.6%), chief financial officer (+10.3%), chief investment officer (+3.7%), general counsel (+8.1%) and other executives (+5.6%).
CEO pay increases were largest at industrial REITs (+20%) and smallest at retail REITs (-2%), which corresponds with the fact that these were also the best and worst performing REIT sectors in terms of TSR performance, respectively.
Regarding equity compensation, time-vested restricted equity with a three-year vesting continue to be the most common equity vehicle, with the use of LTIP units increasing slightly year-over-year. The use of stock options continues to decline.
39% of REITs increased board compensation in 2017 as compared to 33% in 2016. Additionally, for REITs that increased compensation, the median increase also grew from 11% in 2016 to 13% in 2017.
The use of operational metrics for performance shares increased slightly to 37% of REITs from 34% of REITs in 2016. Their use is skewed toward larger REITs, with fewer small cap REITs using non-TSR measures.
In July 2018, FTI Consulting reviewed and analyzed compensation-related disclosure in the 2018 proxy statements for 160 publicly traded REITs, excluding both micro-cap REITs and externally managed companies whose compensation programs are not directly comparable to the broader REIT market. FTI Consulting generally uses the median (as opposed to the average) as the preferred statistical measure for evaluating compensation data trends. The study has been adjusted to include select hotel companies that have not elected to qualify for REIT status for tax purposes but whose operations are comparable to other hotel REITs.


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Tag: jigsaw
Tuesday Recap: in case you missed it, super jigsaw rig, graphic design in progress & other notes
In case you missed any of our spontaneous posts earlier today, here's a quick recap of all the stuff that we got done!
It may look a little strange, but our jigsaw rig Kevin put together has really been a huge help today. Hiba made it through nearly 70 letters — and no wrist pain!
Some final touches like this shim helped us to get it fine-tuned earlier today.
We had the cutting speed fairly high, and initially the jigsaw wasn't quite locked down enough, so our cuts weren't as straight as we would have liked.
However, once we got it all locked down, Hiba started speeding through the letters, which is completely necessary. We have about 400 letters to cut.
But, before that, Lucy came by to starting planning a project / event with Hiba and get up to speed with how things have been moving along here at CIVIC SPACE.
Lucy did a kick ass job with our press releases late last month and we're really happy she's back! This is how she is currently keeping track of things.
It was a full house today, Rosina and Sara came by and double-teamed some design work that needs to get done ASAP in preparation for our launch next Thursday!
We're still pulling from these notes that we took during a meeting a couple weeks ago as we start to assemble a basic schedule design.
Hiba made this note.
I spent the afternoon working on some answers for an interview.
Hiba flipped back to cutting more letters.
The library thus far.
Here's a ribbon from a gift from DodoLab. Reminds me how much I love that gold printing / plating (what is it really called?) reminds me of track and field ribbons.
Snow storm.
Notes on the back of our window facade frame that Kevin came in to continue work on.
Rosina brought a polaroid camera and we instagramed old school.
Also, Rosina started to work with our new stamp as she finessed the design of our library card.
XW.
I took a break and added some bunting to the construction zone in front of our place.
I also painted the jigsaw blades that we had in waiting with more nail polish.
Z!
The remaining letters for the day.
Hiba announcing her record time to cut 4 letters, or 6 letters or something.
The back of our library card being designed.
Kevin further bracing the face of our window facade.
Rosina at work!
Stamp sizing.
Plotting our the date and letters checked-out setup for the back of our letter library card.
The back of the postcard in progress that Sara and I were tossing back and forth.
Broken City Lab in the 1970s.
Tomorrow: some meetings, some guest cutters, and a lot more fun. We're here between 11am and 4pm, if you're in the hood.
Nail polish solution to jigsaw blade visibility troubles
The rig Kevin built has been slightly improved. We added some shims (made of styrofoam) to raise the table top and added this slick coat of red nail polish.
The blade was basically disappearing when we were cutting the styrofoam, so hopefully this fixes it. Also, makes any bloodshed less conspicuous.
Nice lines … thanks table top reverse half ban jig saw!
A Week in the Studio: Some Documentation and Reflections on Last Week at CIVIC SPACE
While we prepare for the launch of CIVIC SPACE on June 21st with the Letter Library project, we're also settling into a routine of being in the space at 411 Pelissier. The idea of having a space of our own is really new to us. Four years after starting BCL by meeting in the classrooms at the School of Visual Arts in the summer, and our backyards, living rooms, and a bunch of coffee shops and restaurants, we're realizing an intensity in our work that was basically impossible before.
Never much of a studio collective, per se, we're now enjoying the shared space and time, and it's impacting everything we're doing. More time together means more time for ideas, concerns, and conversations to work themselves out rather than trying to get through everything in one sitting. In the past, meeting altogether just once a week narrowed our collective time and often translated into a very stop and go process — there was a lot that was happening, but it existed as reports, reflections, or to-do lists that never really got done.
Of course, we're also only experiencing one side of having this time and space together. When CIVIC SPACE launches next week, we'll be entering into a new dynamic with the wider community as well.
This dynamic will be necessarily different than our past projects like Storefront Residencies for Social Innovation — that was a very intense concentrated thirty days of open door programming at a time and in a place that was challenged by the construction happening just outside our doors. CIVIC SPACE will aim to meet and respond to the possibilities of collectivizing around creative responses to the community in front of us.
On the ground, this will translate into fairly regular weekly programming — these will start as small events and opportunities to connect with other people towards exploring art as a position from which we can become engaged in the spatial and civic practices that shift constantly in the background of our experiences of the city.
Of course, the legibility of these events as such will be most pronounced from the longest view of the project. In front of us, these weekly "events" will be simply opportunities to spend time together (and together includes you). Increasingly, we're understanding our work not as a way to fix a city, but as a way to fix the ways that we act (and assume we can act) within it.
But until next week, here's a look at what we're doing and how we're doing it.
First off, Drift v1.5 has been submitted to the App store for approval. While the wait time is something around 7-10 days, it's super exciting to do the actual submission part of it.
Kevin has been working on building a rig for our window so that we can change the window display more frequently, while also keeping it flexible to start screenings.
Remnants of an afternoon of cutting out letters.
Hiba and Rosina working in parallel. Hiba holds a two-sided page of a to-do list. Rosina pulls cards from her wallets as she works on the design of the Letter Library card.
Hiba and I also work on some writing. So early in the process, and so wide. We'll submit later this month to Evental Aesthetics.
Rosina's mastering Illustrator.
Kevin meets more drywall. We built a moveable wall that's still waiting to be moveable. But in the meantime, it's getting a coat of mud and paint.
Just a small number of the letters we'll have ready for you to use as part of our Letter Library project on June 21st.
Hiba showing off her jigsaw skills with an expertly crafted B.
An evening session with Sara, Danielle and Kevin. Felt nice to meet in the space when the street was quiet. It's not always great to have to break up the group so much, but on the other side, often small groups share more, faster.
An early jigsaw rig.
Wall to wall Kevin.
We made a table from MDF and sawhorses, but it's probably our most favourite table ever.
One letter set of Super Scrabble has 200 letters. We're aiming to make two of these.
O, curves.
Josh and Hiba spend Friday afternoon temporarily installing some letters to make this.
Kevin with more drywall mud.
The Letter Library. Some masking tape stuck these styrofoam letters to a brick wall all afternoon. We love how light these are!
Masking tape prep.
Josh places the maiden letter on the wall.
The side of our building.
Up and down the ladder, Josh uses just his eye to line up the entire text.
The brick pattern helped.
Hiba and Josh in the alley.
A serious man.
We're still trying to decide if these letters are going to be painted white, or black, or something else entirely.
Inside, Kevin works the surface of chipboard to a super smooth finish.
Josh's kerning was spot on for Helvetica, but maybe a bit too loose initially for the amount of wall space we had.
So, Josh made a lot of adjustments, but eventually got it all to fit really well.
Between drywall mud layers, Kevin also mocked up this jigsaw rig. Despite our experience with jigsaws (we used them to cut out the letters for Reflect on Here), they get really heavy after a while.
So, we had the idea to basically turn the jigsaw into a half ban saw (or something like that). Kevin went to work on it.
Outside, Josh continues the install.
The letters remaining.
And finally, it's done. We can't wait to see how people use these letters to caption different parts of the city.
Kevin's work on the jigsaw rig …
Crude, but it does the job. He finished the rig later on Friday night and it's now waiting for us to start cutting styrofoam without breaking our wrists. We have to cut about 40 letters a day to hit our target.
We're at the space from about 11am to 4pm everyday. If you're in the neighbourhood, stop by. We're also going to have a painting party to get these letters finished for next Thursday — interested? Let us know.

redpajama_set_name: RedPajamaCommonCrawl


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If you are not in urgent need of assistance, you are welcome to fill out the contact submission form below and one of our coordinators will be in touch with you soon to assist with the registration and donation processes and/or answer any questions that you may have.