Fluoxetine

Fluoxetine is a prescription medicine used to treat the following conditions:

• Depression (known medically as major depressive disorder (MDD) or clinical depression)
• Obsessive compulsive disorder (OCD) 
• Bulimia nervosa 
• Panic disorder 
• Depression associated with bipolar disorder, taken with olanzapine (Symbyax) 
• Treatment-resistant depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Symbyax) 
• Premenstrual Dysphoric Disorder (PMDD)

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of fluoxetine there are no specific foods that you must exclude from your diet when receiving fluoxetine.

• Take fluoxetine exactly as prescribed. Your doctor may need to change (adjust) the dose of fluoxetine until it is right for you.
• If you miss a dose of fluoxetine, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluoxetine at the same time.
• To prevent serious side effects, do not stop taking fluoxetine suddenly. If you need to stop taking fluoxetine, your doctor can tell you how to safely stop taking it.
• If you take too much fluoxetine, call your doctor or poison control center right away, or get emergency treatment.
• Fluoxetine is usually taken once or twice a day, with or without food.
• Fluoxetine is also available as delayed release capsules which can be given once weekly.
• If you do not think you are getting better or have any concerns about your condition while taking fluoxetine, call your doctor.

Take fluoxetine exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dosage of fluoxetine must be individualized based on your age, the condition being treated, other medications you are taking, and other medical conditions you may have.

For adults, fluoxetine doses range from 20 mg to 80 mg, taken once a day or taken as divided doses.

Your doctor may start you on a low dose of fluoxetine and gradually increase your dose.

• It may take more than 4 weeks before you feel the full benefit of fluoxetine.
• Do not stop taking fluoxetine until you talk to your doctor.
• If you need to stop taking fluoxetine, your doctor will probably decrease your dose gradually.

To recommended dose of fluoxetine (Sarafem) for the treatment of Premenstrual Dysphoric Disorder (PMDD) is 20 mg once a day, either every day of the month or on certain days of the month.

When using Fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

Clinical Worsening and Suicide Risk

Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for Major Depressive Disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.15)].

Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Fluoxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

It should be noted that Fluoxetine is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder.

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 (4.1) and Dosage and Administration (2.9, 2.10)]. 

If concomitant use of Fluoxetine with other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan 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.

Allergic Reactions and Rash

In U.S. Fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of Fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.

Since the introduction of Fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, Fluoxetine should be discontinued.

Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression.

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with Fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)].

In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with Fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In U.S. Fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].

Seizures

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with Fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In U.S. Fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. Fluoxetine should be introduced with care in patients with a history of seizures.

Altered Appetite and Weight

Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with Fluoxetine.

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with Fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with Fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with Fluoxetine because of anorexia or weight loss [see Use in Specific Populations (8.4)].

In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with Fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Fluoxetine because of anorexia [see Use in Specific Populations (8.4)].

In U.S. placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with Fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with Fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16 week double-blind trial. Weight change should be monitored during therapy.

Abnormal Bleeding

SNRIs and SSRIs, including Fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

Angle-Closure Glaucoma

Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Hyponatremia

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including Fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of Fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

Anxiety and Insomnia

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with Fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with Fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with Fluoxetine and in 7% of patients treated with placebo.

In U.S. placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with Fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with Fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for Fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S. placebo-controlled Fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5].

QT Prolongation

Postmarketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with Fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased Fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications (4.2), Drug Interactions (7.7, 7.8), Overdose (10.1), and Clinical Pharmacology (12.3)].

Pimozide and thioridazine are contraindicated for use with Fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3)].

Consider ECG assessment and periodic ECG monitoring if initiating treatment with Fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing Fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

Use in Patients With Concomitant Illness

Clinical experience with Fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using Fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiovascular Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received Fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.

Glycemic Control In patients with diabetes, Fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with Fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with Fluoxetine is instituted or discontinued.

Potential for Cognitive and Motor Impairment

As with any CNS-active drug, Fluoxetine has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

Long Elimination Half-Life

Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with Fluoxetine and norFluoxetine following the discontinuation of Fluoxetine [see Clinical Pharmacology (12.3)].

Discontinuation Adverse Reactions

During marketing of Fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the 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.

Fluoxetine and Olanzapine in Combination

When using Fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility.

Monoamine Oxidase Inhibitors (MAOI)

[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2).]

CNS Acting Drugs

Caution is advised if the concomitant administration of Fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)].

Serotonergic Drugs

[See Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2).]

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 SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)].

Electroconvulsive Therapy (ECT)

There are no clinical studies establishing the benefit of the combined use of ECT and Fluoxetine. There have been rare reports of prolonged seizures in patients on Fluoxetine receiving ECT treatment.

Potential for Other Drugs to Affect Fluoxetine

Drugs Tightly Bound to Plasma Proteins Because Fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound Fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)].

Potential for Fluoxetine to Affect Other Drugs

Pimozide Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and Fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and Fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)].

Thioridazine Thioridazine should not be administered with Fluoxetine or within a minimum of 5 weeks after Fluoxetine has been discontinued, because of the risk of QT Prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)].

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.

Thioridazine administration produces a dose-related prolongation of the QT 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.

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, his/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 (4.2)].

Tricyclic Antidepressants (TCAs) In 2 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 TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when Fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Benzodiazepines The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and Fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Antipsychotics Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant Fluoxetine.

Anticonvulsants Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant Fluoxetine treatment.

Lithium 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 [see Warnings and Precautions (5.2)].

Drugs Tightly Bound to Plasma Proteins Because Fluoxetine is tightly bound to plasma proteins, the administration of Fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin®, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)].

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.

Additionally, 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.

Olanzapine Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

When using Fluoxetine and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Drugs That Prolong the QT Interval

Do not use Fluoxetine in combination with thioridazine or pimozide. Use Fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of Fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of Fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

See the FDA-approved Medication Guide.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Fluoxetine as monotherapy. When using Fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

General Information

Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with Fluoxetine and to reread it each time the prescription is renewed.

Healthcare providers 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. Healthcare providers 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.

Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking Fluoxetine.

When using Fluoxetine and olanzapine in combination, also refer to the Medication Guide for Symbyax.

Clinical Worsening and Suicide Risk

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 [see Box Warning and Warnings and Precautions (5.1)].

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)].

Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Allergic Reactions and Rash

Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Abnormal Bleeding

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 Warnings and Precautions (5.7) and Drug Interactions (7.4)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking Fluoxetine.

Angle-Closure Glaucoma

Patients should be advised that taking Fluoxetine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Preexisting 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 [see Warnings and Precautions (5.8)].

Hyponatremia

Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Fluoxetine. 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 [see Warnings and Precautions (5.9)].

QT Prolongation

Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with Fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions (5.11)].

Potential for Cognitive and Motor Impairment

Fluoxetine may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.13)].

Use of Concomitant Medications

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax® (olanzapine and Fluoxetine hydrochloride capsules), Sarafem® (Fluoxetine capsules), or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on Fluoxetine.

Discontinuation of Treatment

Patients should be advised to take Fluoxetine exactly as prescribed, and to continue taking Fluoxetine as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking Fluoxetine without consulting their physician [see Warnings and Precautions (5.15)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with Fluoxetine.

Use in Specific Populations

Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Nursing Mothers Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because Fluoxetine is excreted in human milk, nursing while taking Fluoxetine is not recommended [see Use in Specific Populations (8.3)].

Pediatric Use of Fluoxetine Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of Fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving Fluoxetine [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)].

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. AE 9/2016

• PROzac
• PROzac Weekly [DSC]
• Sarafem

The half-life for fluoxetine and norfluoxetine is prolonged.

Note: Commercial oral solution is available (4 mg/mL)

A 1 mg/mL fluoxetine oral solution may be prepared using the commercially available preparation (4 mg/mL). In separate graduated cylinders, measure 5 mL of the commercially available fluoxetine preparation and 15 mL of Simple Syrup, NF. Mix thoroughly in incremental proportions. For a 2 mg/mL solution, mix equal proportions of both the commercially available fluoxetine preparation and Simple Syrup, NF. Label "refrigerate". Both concentrations are stable for up to 56 days.

All dosage forms should be stored at controlled room temperature. Protect from light.

Adverse events have been observed in animal reproduction studies. Fluoxetine and its metabolite cross the human placenta. Available studies evaluating teratogenic effects following maternal use of fluoxetine in the first trimester have shown inconsistent results. An increased risk of cardiovascular events was observed in one study; however, no specific pattern was observed and a causal relationship has not been established. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SSRIs/SNRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary hypertension of the newborn (PPHN) has also been reported with SSRI exposure. The long-term effects of in utero SSRI exposure on infant development and behavior are not known.

Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of fluoxetine to achieve euthymia. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy.

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, dry mouth, fatigue, diarrhea, nightmares, insomnia, loss of strength and energy, hot flashes, flu-like symptoms, or yawning. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), agitation, irritability, panic attacks, behavioral changes, mood changes, tachycardia, abnormal heartbeat, dizziness, passing out, excessive weight gain, excessive weight loss, sexual dysfunction, decreased libido, seizures, change in amount of urine passed, shortness of breath, vision changes, eye pain, eye irritation, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

You should not use fluoxetine if you also take pimozide or thioridazine, or if you are being treated with methylene blue injection.

Do not use fluoxetine if you have used an MAO inhibitor in the past 14 days, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine.

You must wait at least 14 days after stopping an MAO inhibitor before you can take fluoxetine. You must wait 5 weeks after stopping fluoxetine before you can take thioridazine or an MAOI.

Some young people have thoughts about suicide when first taking an antidepressant. Stay alert to changes in your mood or symptoms.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Get emergency medical help if you have signs of an allergic reaction to fluoxetine: skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have:

• blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;

• high levels of serotonin in the body--agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;

• low levels of sodium in the body--headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;

• severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common fluoxetine side effects may include:

• sleep problems (insomnia), strange dreams;

• headache, dizziness, vision changes;

• tremors or shaking, feeling anxious or nervous;

• pain, weakness, yawning, tired feeling;

• upset stomach, loss of appetite, nausea, vomiting, diarrhea;

• dry mouth, sweating, hot flashes;

• changes in weight or appetite;

• stuffy nose, sinus pain, sore throat, flu symptoms; or

• decreased sex drive, impotence, or difficulty having an orgasm.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Liver dysfunction (including cirrhosis):
-Immediate-release oral formulations: Lower or less frequent dosing may be appropriate in these patients
-Delayed-release oral capsules: Data not available

Use of this drug is not recommended; however, if it is required by the mother, it is not considered a reason to discontinue breastfeeding Excreted into human milk: Yes Comments: -Breastfed infants should be monitored for side effects such as colic, fussiness, sedation, and adequate weight gain. -Mothers taking an SSRI during pregnancy and postpartum may have difficulty breastfeeding and may require additional breastfeeding support.

The average amount of drug in breastmilk is higher with fluoxetine than with most other SSRIs, and the long-acting active metabolite, norfluoxetine, is detectable in the serum of most breastfed infants during the first 2 months postpartum and in a few thereafter. No adverse effects on development have been reported in a few infants followed for up to one year. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective. Alternatively, medicines with a lower excretion into breastmilk may be preferred, particularly when nursing a newborn or preterm infant. An infant breastfed by a mother receiving oral fluoxetine therapy developed crying, sleep disturbance, watery stools, and vomiting. The infants' plasma drug levels of fluoxetine and norfluoxetine on the second day of feeding were 340 ng/mL and 208 ng/mL, respectively. A report of ten women nursing eleven infants found that less than 10% of the dose of fluoxetine (per kg of body weight) was delivered to the nursing infant during chronic maternal therapy. Other reports from two lactating women taking fluoxetine have described milk fluoxetine and norfluoxetine concentrations to be about one-fifth to one-quarter of the serum concentrations. No adverse effects were reported in these nursing infants.

Summary of Use during Lactation

The average amount of drug in breastmilk is higher with fluoxetine than with most other SSRIs and the long-acting, active metabolite, norfluoxetine, is detectable in the serum of most breastfed infants during the first 2 months postpartum and in a few thereafter. Adverse effects such as colic, fussiness, and drowsiness have been reported in some breastfed infants. Decreased infant weight gain was found in one study, but not in others. No adverse effects on development have been found in a few infants followed for up to a year.

If fluoxetine is required by the mother, it is not a reason to discontinue breastfeeding. If the mother was taking fluoxetine during pregnancy or if other antidepressants have been ineffective, most experts recommend against changing medications during breastfeeding. Otherwise, agents with lower excretion into breastmilk may be preferred, especially while nursing a newborn or preterm infant. The breastfed infant should be monitored for behavioral side effects such as colic, fussiness or sedation and for adequate weight gain. Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding and may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants.

Drug Levels

Fluoxetine is metabolized to norfluoxetine which has antidepressant activity that is considered to be equal to fluoxetine.[1]

Maternal Levels. In a pooled analysis of serum levels from published studies and 1 unpublished case, the authors found that 20 mothers taking an average daily dosage of 28 mg (range 10 to 80 mg) had an average milk fluoxetine level of 76 mcg/L (range 23 to 189 mcg/L).[1] Using the average dosage and milk level data from this paper, an exclusively breastfed infant would receive an estimated 2.4% of the maternal weight-adjusted dosage of fluoxetine; however, the substantial contribution of norfluoxetine was not considered. In one of the studies included in the pooled analysis that measured both fluoxetine and norfluoxetine in 14 mothers, the average daily infant dosage in breastmilk was about 7% (range 3 to 12%) of the mother's weight-adjusted dosage.[1]

Eleven women taking fluoxetine 20 to 40 mg daily during pregnancy and lactation had trough milk fluoxetine and norfluoxetine levels measured on day 4, week 2 and month 2 postpartum. When standardized to a 20 mg daily dosage, total drug concentration in breastmilk ranged from 75.4 to 91.5 mcg/L at the 3 times. The authors estimated that an exclusively breastfed infant would receive a minimum of 2.4% and 3.8% of the maternal weight-adjusted dosage of the drug and metabolite combined with this maternal dosage regimen at 2 weeks and 2 months of age, respectively.[2]

In 1 mother who was 11 weeks postpartum and taking fluoxetine in a daily dosage of 20 mg, the authors estimated that an exclusively breastfed infant would receive 3.3% of the maternal weight-adjusted dosage.[3]

At 2 months postpartum, 7 mothers taking an average of 24 mg of fluoxetine daily had average breastmilk levels of 63.7 mcg/L of fluoxetine and 103.8 mcg/L of norfluoxetine. These data indicate that a fully breastfed infant would receive 25 mcg/kg daily of fluoxetine plus norfluoxetine. This value would be about 6.3% of the maternal weight-adjusted dosage.[4]

Twenty-three nursing mothers who were taking fluoxetine in an average dose of 21 mg daily for a minimum of 4 weeks and averaging 3.7 months postpartum had random foremilk samples (n = 30) analyzed for R- and S-isomers of fluoxetine and norfluoxetine. The weight-adjusted dosages of these infants (average 91% breastfed) were calculated to be 0.54% and 0.57% of the maternal weight-adjusted dosage for fluoxetine and norfluoxetine, respectively. The concentrations of the active S-isomer in milk were about 1.9 times that of the R- isomer.[5]

Data from 24 women on the excretion of fluoxetine and norfluoxetine into milk from two previously published studies[6][7] were combined and reanalyzed using NONMEM. Data from the two original papers were previously included in a pooled analysis reported above.[1] Simulations of the data indicated that a fully breastfed infant would receive a median of 0.017 mg/kg daily of fluoxetine plus norfluoxetine. This resulted in a median weight-adjusted percentage of 5.9% of the maternal dosage, with a 99th percentile value of 23%.[8]

Four women taking fluoxetine 20 mg daily had an average breastmilk fluoxetine concentration of 51 mcg/L at times that were not stated. These values equated to an average infant dosage of 7.6 mcg/kg daily or 2.2% of the maternal weight-adjusted dosage.[9]

A nursing mother was taking fluoxetine 20 mg daily. Foremilk and hindmilk samples taken at 1 week postpartum, 2 hours after a dose contained 19 mcg/L and 16 mcg/L, respectively. The samples also contained 36 mcg/L and 30 mcg/L of norfluoxetine in foremilk and hindmilk, respectively.[10]

Infant Levels. In a pooled analysis of 22 mother-infant pairs from published and unpublished cases, the authors found that infants had an average of 7% (range 0 to 59%) of their mothers' fluoxetine plasma levels; 4 of the 22 infants (18%) had a plasma level greater than 10% of the mothers' which was defined by the authors as being elevated.[1]

Eleven breastfed (6 exclusively; 5 supplemented) infants with an average age of 24.6 weeks (range 5 to 36 weeks) whose mothers were taking an average of 27.3 mg daily of fluoxetine all had measurable norfluoxetine serum levels averaging 3.2 mcg/L (range 1.4 to 8.7 mcg/L) which was 3.2% of average maternal norfluoxetine serum levels. One infant also had a detectable fluoxetine level of 2.6 mcg/L.[11]

The breastfed (extent not stated) infants of 11 women taking fluoxetine 20 to 40 mg daily during pregnancy and lactation had trough milk fluoxetine and norfluoxetine levels measured on day 4, week 2 and month 2 postpartum. At 2 weeks of age, fluoxetine was detectable in the serum of 2 of the infants in concentrations of 7.1% of the average maternal serum level. Norfluoxetine was detectable in the serum of all infants in average concentrations of 38% of the average maternal serum level. At 2 months of age, no infant had detectable fluoxetine levels; norfluoxetine was detectable in the serum of all infants in concentrations averaging 6.5% of the average maternal serum level.[2]

At 2 months postpartum, the breastfed infants of 7 mothers taking an average of 24 mg of fluoxetine daily had an average serum levels of 2 mcg/L of fluoxetine and 8.5 mcg/L of norfluoxetine which was about 9% of the maternal serum norfluoxetine level.[4]

Thirty serum levels were obtained from 23 infants with an average age of 3.7 months and breastfed an average of 91% by mothers who had been taking fluoxetine in an average dose of 21 mg daily for at least 4 weeks. Six of 7 infants had detectable serum levels in the first month, 6 of 8 in the second month and 2 of 14 thereafter. The ratio of infant to maternal serum levels of fluoxetine plus S-norfluoxetine dropped rapidly during the first month and was less than 10% by 2 months of age. Infant serum levels of S-fluoxetine and S-norfluoxetine were about 3 times as high as the R-isomers during the first 2 months. Only norfluoxetine could be detected after this time and the S- to R-isomer ratio fell to about 1.4.[5]

Effects in Breastfed Infants

Colic, decreased sleep, vomiting and watery stools occurred in a 6-day-old breastfed infant probably caused by maternal fluoxetine.[12] Two other reports of colic in breastfed infants, a 1.76-month-old and a 2-month-old, were possibly caused by fluoxetine in breastmilk. The older of the two also exhibited hyperactivity.[7]

Another case of possible increased irritability in a 3-month-old was noted by one pediatrician observer; however, the mother and another pediatrician disagreed.[13]

Occurrence of hyperglycemia and glycosuria in a 5-month-old, possibly from fluoxetine in breastmilk was reported to the Australian Adverse Drug Reaction Advisory Committee.[14]

A 3-day-old breastfed infant was difficult to arouse, ceased rooting behavior, decreased nursing, and was moaning and grunting. Although the infant had been exposed in utero and was somewhat drowsy during the first 2 days of life, symptoms became worse after the mother's milk came in on day 3. These effects were probably caused by fluoxetine in breastmilk.[15]

Possible drug-induced seizure-like activity and cyanosis occurred in a breastfed 3-week-old breastfed infant whose mother was taking fluoxetine, carbamazepine and buspirone during pregnancy and breastfeeding.[16]

One observational report of 4 infants found no apparent neurological abnormalities following exposure to fluoxetine in milk for 12 to 52 weeks.[17]

A retrospective, case-control, cohort study compared the weights of the infants of mothers who took fluoxetine during pregnancy and breastfed for at least 2 weeks postpartum to the infants of mothers who took fluoxetine during pregnancy and did not breastfeed. Compared to controls, decreased weight gain occurred among the 26 infants exposed postpartum to fluoxetine in breastmilk, although the weights were still in the normal range.[18]

A prospective study of 51 nursing women taking fluoxetine and 63 nursing women who took no fluoxetine found no effect on weight gain, but reported a greater frequency of unspecified side effects in the infants of mothers who took fluoxetine.[19] This study's results have been reported only in abstract form, so some details are lacking.

In a prospective study of 40 women who took fluoxetine throughout pregnancy, 21 breastfed their infants (extent and duration not stated). Testing of the infants at 15 to 71 months of age found no differences in cognitive, language or temperament measurements between infants who were breastfed and those who were not.[20]

In a study comparing the 31 infants of depressed mothers who took an SSRI during pregnancy for major depression with 13 infants of depressed mothers who did not take an SSRI, mental development and most motor development in both groups was normal at follow-up averaging 12.9 months. Three of the treated mothers took fluoxetine in doses averaging 23.3 mg daily for an average of 3 months while breastfeeding their infants. Psychomotor development was slightly delayed compared to controls, but the contribution of breastfeeding to abnormal development could not be determined.[21]

Platelet serotonin levels were measured in 11 mothers and their breastfed infants after 4 to 12 weeks of fluoxetine therapy. Maternal dosages ranged from 20 to 40 mg daily. Ten of the infants were under 6 months of age and 4 were under 3 months of age at the start of therapy; 6 were exclusively breastfed. Although maternal platelet serotonin levels were decreased from 157 mcg/L to 23 mcg/L by fluoxetine therapy, average infant serotonin levels were 217 mcg/L before and 230 mcg/L after maternal therapy. These findings indicate that the amount of fluoxetine ingested by the infants was not sufficient to affect serotonin transport in platelets in most breastfed infants. However, 3 infants experienced drops in platelet serotonin of 13, 24 and 60%, respectively. The latter infant was the only one with measurable fluoxetine plasma levels as well as norfluoxetine, but had no discernible adverse effects. One other infant had a delay in motor development at 24 weeks, but had normal mental development; 6 other infants were within 1 standard deviation of normal in both measures when tested between 24 and 56 weeks of age. Platelets and neurons both have the same serotonin transporter, so this effect on platelet serotonin might indicate potential effects on the nervous system of some breastfed infants.[11]

Twenty-nine mothers who took fluoxetine in an average dosage of 34.6 mg daily for depression or anxiety starting no later than 4 weeks postpartum, breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and mothers reported no abnormal effects in their infants.[22]

One study of side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention in one infant whose mother was taking fluoxetine. No specific information on maternal fluoxetine dosage, extent of breastfeeding or infant age was reported.[23]

Eleven infants who were breastfed (extent and duration not stated) during maternal use of fluoxetine for depression (n = 5) or panic disorder (n = 6) had normal weight gain at 12 months of age that was not significantly different from a control group of infants whose mothers took no psychotropic medications. Neurologic development was also normal at 12 months of age.[2]

In 1 breastfed (extent not stated) infant aged 11 weeks whose mother was taking fluoxetine 20 mg daily, no adverse reactions were noted clinically at the time of the study.[3]

A small study compared the reaction to pain in infants of depressed mothers who had taken an SSRI during pregnancy alone or during pregnancy and nursing to a control group of unexposed infant of nondepressed mothers. Infants exposed to an SSRI either prenatally alone or prenatally and postnatally via breastmilk had blunted responses to pain compared to control infants. Seven of the 30 infants were exposed to fluoxetine. Because there was no control group of depressed, nonmedicated mothers, an effect due to maternal behavior caused by depression could not be ruled out. The authors stressed that these findings did not warrant avoiding drug treatment of depression during pregnancy or avoiding breastfeeding during SSRI treatment.[4]

An infant was born to a mother taking fluoxetine 40 mg daily, oxycodone 20 mg 3 times daily, and quetiapine 400 mg daily. The infant was breastfed 6 to 7 times daily and was receiving 120 mcg of oral morphine 3 times daily for opiate withdrawal. Upon examination at 3 months of age, the infant's weight was at the 25th percentile for age, having been at the 50th percentile at birth. The authors attributed the weight loss to opiate withdrawal. The infant's Denver developmental score was equal to his chronological age.[24]

An uncontrolled online survey compiled data on 930 mothers who nursed their infants while taking an antidepressant. Infant drug discontinuation symptoms (e.g., irritability, low body temperature, uncontrollable crying, eating and sleeping disorders) were reported in about 10% of infants. Mothers who took antidepressants only during breastfeeding were much less likely to notice symptoms of drug discontinuation in their infants than those who took the drug in pregnancy and lactation.[25]

A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Fifteen of the infants were exposed to fluoxetine in utero.[26]

A late preterm infant was born to a mother who took fluoxetine 60 mg daily throughout pregnancy and during exclusive breastfeeding. At 7 days of age, the infant was found to be having jerking movements, with hypertonia and hyperreflexia as well as tachypnea and compensated metabolic acidosis. The infant's Finnegan scores were the range of 7 to 10. On day 8 of life, the infant had a serum fluoxetine level of 120 mcg/L, which is similar to therapeutic adult levels. Breastfeeding was discontinued and after 5 days of formula feeding the infant's Finnegan scores had decreased to a range of 3 to 6. After 10 days of formula, most symptoms had subsided. At 3 months of age, the infant was growing and developing normally. The infant's symptoms were attributed to serotonin syndrome caused by the high levels of fluoxetine rather than to withdrawal.[27] The reaction was probably caused by fluoxetine and breastfeeding might have contributed to maintaining the high fluoxetine levels after birth.

A woman with narcolepsy took sodium oxybate 4 grams each night at 10 pm and 2 am as well as fluoxetine 20 mg and cetirizine 5 mg daily throughout pregnancy and postpartum. She breastfed her infant except for 4 hours after the 10 pm oxybate dose and 4 hours after the 2 am dose. She either pumped breastmilk or breastfed her infant just before each dose of oxybate. The infant was exclusively breastfed or breastmilk fed for 6 months when solids were introduced. The infant was evaluated at 2, 4 and 6 months with the Ages and Stages Questionnaires, which were withing the normal range as were the infant's growth and pediatrician's clinical impressions regarding the infant's growth and development.[28]

Effects on Lactation and Breastmilk

Fluoxetine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients.[29][30][31][32][33][34][35][36] Euprolactinemic galactorrhea has also been reported.[37] In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, fluoxetine was found to have a 3.6-fold increased risk of causing hyperprolactinemia compared to other drugs.[33] Preliminary animal and in vitro studies found that fluoxetine may have some estrogenic activity.[34] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior compared to the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum.[35]

A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups.[36]

An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 30% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge.[38] The antidepressants used by the mothers were not specified.

Alternate Drugs to Consider

Nortriptyline, Paroxetine, Sertraline

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