PROZAC (fluoxetine) is indicated for the symptomatic relief of Major Depressive Disorder (MDD).

PROZAC has been shown to significantly decrease binge-eating and purging activity when compared with placebo treatment.

PROZAC is indicated for the symptomatic treatment of obsessive-compulsive disorder (OCD).

The obsessions or compulsions must be experienced as intrusive, markedly distressing, time consuming, or interfering significantly with the person's social or occupational functioning.

The efficacy of PROZAC in hospitalized patients has not been adequately studied.

The effectiveness of PROZAC in long-term use in bulimia nervosa (i.e. for more than 16 weeks) and in obsessive-compulsive disorder (i.e. for more than 13 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use PROZAC in these indications for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Evidence from clinical studies and experience suggests that use in the geriatric population may be associated with differences in safety or effectiveness, and a brief discussion can be found in the appropriate sections (Warnings and Precautions, Special Populations, Geriatrics (≥60 years of age); Dosage and Administration).

PROZAC is not indicated for use in patients below the age of 18 years. See Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; see also Dosage and Administration.

PROZAC (fluoxetine) is contraindicated in patients with known hypersensitivity to the drug or the excipients of the product. For a complete listing, see Dosage Forms, Composition and Packaging.

There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving PROZAC, or other serotonin reuptake inhibitors (SSRIs), in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued PROZAC and then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome (e.g., serotonin syndrome). Therefore, PROZAC should not be used in combination with an MAOI, including either within a minimum of 14 days of discontinuing therapy with an MAOI, or a minimum of 5 weeks of discontinuing therapy with PROZAC. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping PROZAC before starting an MAOI. Limited reports suggest that intravenously administered dantrolene (Dantrium) or orally administered cyproheptadine (Periactin) may benefit patients experiencing such reactions. See Drug Interactions.

Thioridazine should not be administered concomitantly with PROZAC or within a minimum of 5 weeks after PROZAC has been discontinued, nor should PROZAC be administered within 2 weeks after thioridazine has been discontinued.

Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related.

An in vivo study suggests that drugs which inhibit P4502D₆, including certain SSRI's such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, PROZAC should not be used in combination with thioridazine. See Drug Interactions.

Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer anti-depressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Patients currently taking SSRIs or newer anti-depressants should not be discontinued abruptly, due to risk of discontinuation symptoms. PROZAC has only rarely been associated with such symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation, except for fluoxetine, is recommended. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy which makes dose tapering unnecessary in most patients taking this drug (see Warnings and Precautions, Dependence; Adverse Reactions, Adverse Events Subsequent to Discontinuation; and Dosage and Administration, Discontinuation of Treatment).

Because of the long elimination half-lives of fluoxetine and its major active metabolite norfluoxetine, 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 Action and Clinical Pharmacology; and Dosage and Administration). Even when dosing is stopped, active drug substance will persist in the body for weeks due to the long elimination half-lives of fluoxetine and norfluoxetine. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following discontinuation of PROZAC.

Post-marketing reports indicate that some neonates exposed to PROZAC, other SSRIs (selective serotonin reuptake inhibitors), or newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with PROZAC during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Warnings and Precautions, Special Populations, Pregnant Women; and Dosage and Administration).

Significant weight loss, especially in underweight depressed patients and the elderly, may be an undesirable result of treatment with PROZAC. PROZAC should be given with caution to patients suffering from anorexia nervosa and only if the expected benefits (e.g. co-morbid depression) markedly outweigh the potential weight reducing effect of the drug.

Patients should be cautioned against driving an automobile or performing hazardous tasks until they are reasonably certain that treatment with PROZAC does not affect them adversely.

During premarketing testing, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among these cases, 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 these allergic reactions include rash, 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 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 severe desquamation that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness.

Since the introduction of fluoxetine, 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, PROZAC should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.

The following additional Precautions are listed alphabetically.

PROZAC 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 premarketing clinical studies. Retrospective evaluation of EKGs in some of these studies showed no conduction abnormalities that resulted in heart block. The mean heart rate was reduced by approximately 3 beats/minute.

Self-induced vomiting often leads to hypokalemia which may lower seizure threshold and/or may lead to cardiac conduction abnormalities. Electrolyte levels of bulimic patients should be assessed prior to initiation of treatment.

Clinical experience with PROZAC in patients with concomitant systemic illness is limited and it should be used cautiously in such patients, especially those with diseases or conditions that could affect metabolism or hemodynamic responses.

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia or other symptoms which may be of clinical significance).

PROZAC (fluoxetine) has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients (see Warnings and Precautions, General; Adverse Reactions; and Dosage and Administration).

PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PROZAC.

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.

There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking fluoxetine. While there have been reports of abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had a causative role.

Since clearances of fluoxetine and norfluoxetine may be decreased in patients with impaired liver function including cirrhosis, a lower or less frequent dose should be used in such patients. See Action and Clinical Pharmacology.

PROZAC should be used with caution in patients with a history of convulsive disorders. The incidence of seizures associated with fluoxetine during clinical trials did not appear to differ from that reported with other marketed antidepressants; however, patients with a history of convulsive disorders were excluded from these trials.

Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, including PROZAC, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with PROZAC should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. PROZAC should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John's Wort) due to the risk of serotonergic syndrome (see Contraindications and Drug Interactions).

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. As with other drugs with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviors have been reported during fluoxetine therapy or early after treatment discontinuation. Close supervision of high-risk patients should accompany drug therapy and consideration should be given to the possible need for hospitalization. Physicians should encourage patients of all ages to report any new or worsened distressing thoughts or feelings occurring at any time. In order to minimize the opportunity for overdosage, prescriptions for fluoxetine should be written for the smallest quantity of drug consistent with good patient management.

Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

During premarketing clinical trials in a patient population comprised primarily of unipolar depressed patients, hypomania or mania occurred in approximately 1% of fluoxetine treated patients. The incidence in a general patient population which might also include bipolar depressives is unknown. The likelihood of hypomanic or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

There are no clinical studies to support the safety and efficacy of combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

Since fluoxetine is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. However, until an adequate number of patients with severe renal impairment have been evaluated in the course of chronic treatment, fluoxetine should be used with caution in such patients.

Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when PROZAC was discontinued. Although these cases were complex with varying possible etiologies, some were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in older patients and in patients taking diuretics or who were otherwise volume depleted.

In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration of sodium in a fluoxetine treated patient was 129 mmol/L. The observed decreases were not clinically significant.

Safe use of fluoxetine during pregnancy has not been established. Therefore PROZAC should not be administered to women of childbearing potential unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus or the child.

Post-marketing reports indicate that some neonates exposed to PROZAC, other SSRIs (selective serotonin reuptake inhibitors), or newer anti-depressants 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 other newer anti-depressants or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Contraindications, Monoamine Oxidase Inhibitors). When treating a pregnant woman with PROZAC during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration).

PROZAC and its metabolites are excreted in breast milk, and have been observed to reach high levels in the plasma of nursing infants. Women who are taking PROZAC should not breast feed unless, in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored.

In one breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, a 6-week infant, nursed by a mother on PROZAC, developed crying, decreased sleep, vomiting and watery stools. The breast milk showed concentrations of 69 ng/mL for fluoxetine and 90 ng/mL for norfluoxetine. In the infant's plasma, the concentrations of fluoxetine and norfluoxetine on the second day of feeding were 340 and 208 ng/mL, respectively.

PROZAC is not indicated for use in patients below the age of 18 years. See Warnings and Precaution, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm. See also Dosage and Administration, Pediatrics; and Indications and Clinical Use, Pediatrics (<18 years of age).

Evaluation of patients over the age of 60 who received PROZAC 20 mg daily revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. These data are however insufficient to rule out possible age-related differences during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs. See Indications and Clinical Use, and Dosage and Administration.

In clinical trials, the most commonly observed adverse events associated with the use of PROZAC (fluoxetine) and not seen at an equivalent incidence among placebo treated patients were: central nervous system complaints, including headache, nervousness, insomnia, drowsiness, fatigue or asthenia, anxiety, tremor, and dizziness or lightheadedness; gastrointestinal complaints, including nausea, diarrhea, dry mouth and anorexia; and excessive sweating.

Fifteen percent of approximately 4000 patients who received PROZAC in North American clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation from depression trials in adults and elderly, included: psychiatric, primarily nervousness, anxiety, and insomnia; digestive, primarily nausea; nervous system, primarily dizziness, asthenia, and headaches; skin, primarily rash and pruritus.

In obsessive compulsive disorder studies, 12.1% of fluoxetine treated patients discontinued treatment early because of adverse events. Anxiety and rash, at incidences of less than 2%, were the most frequently reported events. In bulimia nervosa studies, 10.2% of fluoxetine treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidences of less than 2%, were the most frequently reported events.

Symptoms associated with discontinuation of PROZAC have been reported in clinical trials and post-marketing (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia, or other symptoms which may be of clinical significance). The majority of these are mild and self-limiting. PROZAC (fluoxetine) has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients. See Warnings and Precautions, General; and Dosage and Administration.

Suicidal thoughts and acts are far more common among depressed patients than in the general population. It is estimated that suicide is 22 to 36 times more prevalent in depressed persons than in the general population. A comprehensive meta-analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder compared fluoxetine (n=1765) with a tricyclic antidepressant (n=731) or placebo (n=569), or both. The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants.

In countries where the drug has already been marketed, the following potentially serious adverse reactions have been reported; interactions with MAO inhibitors and possibly other drugs, allergic reactions, cardiovascular reactions, syndrome of inappropriate ADH secretion, and grand mal seizure. Death and life-threatening events have been associated with some of these reactions, although causal relationship to PROZAC has not necessarily been established.

Post-marketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with PROZAC including allergic skin reactions.

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Multiple doses of PROZAC had been administered to 10 782 patients with various diagnoses in US clinical trials as of May 8, 1995. 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 Table 1, Table 2 and Table 3 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.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. See Table 1.

Table 1: PROZAC

Treatment-emergent Adverse Events Incidence in Fluoxetine versus Placebo Trials Listed by Indication

^a. The most common treatment-emergent adverse events associated with the use of PROZAC (incidence of at least 5% for PROZAC and at least twice that for placebo within at least one of the indications) for the treatment of depression, OCD, and bulimia in US controlled clinical trials.
^b. Denominator used was for males only (N=690 PROZAC depression; N=410 placebo depression; N=116 PROZAC OCD; N=43 placebo OCD; N=14 PROZAC bulimia; N=1 placebo bulimia).

Legend:

Table 2 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with PROZAC and with incidence greater than placebo who participated in US controlled clinical trials comparing PROZAC with placebo in the treatment of depression, OCD, or bulimia. Table 2 provides combined data for the pool of studies that are provided separately by indication in Table 1.

Table 2: PROZAC

Combined Treatment-emergent Adverse Events Incidence for Patients Treated with PROZAC versus Placebo

^a. Included are events reported by at least 2% of patients taking PROZAC, except the following events, which had an incidence on placebo >PROZAC (depression, OCD, and bulimia combined): abdominal pain, abnormal dreams, accidental injury, back pain, chest pain, constipation, cough increased, depression (includes suicidal thoughts), dysmenorrhea, gastrointestinal disorder, infection, myalgia, pain, paresthesia, rhinitis, sinusitus, thinking abnormal.

Legend:

Table 3 lists the adverse events associated with discontinuation of PROZAC treatment (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary event associated with discontinuation) in depression, OCD, and bulimia. For symptoms associated with discontinuation of PROZAC in clinical trials and post-marketing, see Adverse Reaction, Post-Market Adverse Drug Reactions.

Table 3: PROZAC

Adverse Events Associated with Discontinuation of PROZAC Treatment

Depression, OCD, and Bulimia Combined (N=1108)	Depression (N=392)	OCD (N=266)	Bulimia (N=450)
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