Home > Psicotherapeutic Drugs > Antidepressants > Fluoxetine

BRAND NAME: PROZAC

DRUG CLASS: Selective Serotonin Reuptake Inhibitor (SSRI)

CLINICAL EFFECTS: Antidepressant, Antipanic, Antiobsessional and Antibulimic 

IMPORTANT WARNING:
Studies have shown that children and teenagers who take antidepressants ('mood elevators') such as fluoxetine may be more likely to think about harming or killing themselves or to plan or try to do so than children who do not take antidepressants.If your child’s doctor has prescribed fluoxetine for your child, you should watch his or her behavior very carefully, especially at the beginning of treatment and any time his or her dose is increased or decreased. Your child may develop serious symptoms very suddenly, so it is important to pay attention to his or her behavior every day. Call your child’s doctor right away if he or she experiences any of these symptoms: new or worsening depression; thinking about harming or killing him- or herself or planning or trying to do so; extreme worry; agitation; panic attacks; difficulty falling or staying asleep; irritability; aggressive behavior; acting without thinking; severe restlessness; frenzied abnormal excitement, or any other sudden or unusual changes in behavior.Your child’s doctor will want to see your child often while he or she is taking fluoxetine, especially at the beginning of his or her treatment .Your child’s doctor may also want to speak with you or your child by telephone from time to time. Be sure that your child keeps all appointments for office visits or telephone conversations with his or her doctor.Your child's doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when your child begins treatment with fluoxetine. Read the information carefully and ask your child's doctor or pharmacist if you have any questions.
You also can obtain the Medication Guide from the FDA website: http://www.fda.gov/cder/drug/antidepressants/MG_template.pdf.
Talk to your child’s doctor about the risks of giving fluoxetine to your child.

CLINICAL PHARMACOLOGY

INDICATIONS

DOSAGE

PHARMACOKINETICS

CONTRAINDICATIONS

WARNINGS

PRECAUTIONS

SIDE EFFECTS

CONTRAINDICATIONS:       
In patients with known hypersensitivity to the drug.

MAO Inhibitors:
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 fluoxetine in combination with a MAO inhibitor and in patients who have recently discontinued fluoxetine and then started on a MAO inhibitor. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with a MAO inhibitor or within 14 days of discontinuing therapy with a MAO inhibitor. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting a MAO inhibitor. Limited reports suggest that i.v. administered dantrolene or orally administered cyproheptadine may benefit patients experiencing such reactions.

WARNINGS:     
Allergic Reactions (Rash and Accompanying Events):
During premarketing testing of more than 5600 patients given fluoxetine, approximately 4% developed a rash 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 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 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, 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, 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 allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.

Implications of the Long Elimination Half-Life of Fluoxetine:
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 Pharmacology and Dosage). 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 fluoxetine.

PRECAUTIONS:       
Anxiety and Insomnia:
During premarketing clinical trials, anxiety, nervousness and insomnia were reported by 10 to 15% of patients treated with fluoxetine. These symptoms led to discontinuation of the drug in 5% of the patients.

Weight Change:
Significant weight loss, especially in underweight depressed patients, may be an undesirable result of treatment with fluoxetine.

Mania/Hypomania:
During premarketing clinical trials in a patient population comprised primarily of unipolar depressives, 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.

Seizures:
Fluoxetine 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 a prolonged seizure in patients on fluoxetine receiving ECT treatment.

Hypokalemia:
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.

Suicide:
The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. 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.

Concomitant Illness:
Clinical experience with fluoxetine 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.

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 premarketing clinical studies. Retrospective evaluation of ECGs 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.

Fluoxetine 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.

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.

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

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.

Hyponatremia:
Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared to be reversible when fluoxetine 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.

Platelet Function:
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.

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

Pregnancy and Lactation:
Safe use of fluoxetine during pregnancy and lactation has not been established. Therefore, it should not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child or fetus. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295 ng/mL. No adverse effects on the infant were reported.

Children:
Safety and effectiveness in patients below the age of 18 have not been established.

Geriatrics:
Elderly patients should initially receive fluoxetine in low dosage with slow progressive increases only if required and tolerated. Patients who have concomitant systemic illnesses or who are receiving other drugs concomitantly should be under careful observation at all dosage levels.

SIDE EFFECTS:        
Commonly Observed:
In clinical trials, the most commonly observed adverse events associated with the use of fluoxetine and not seen at an equivalent incidence among placebo treated patients were: CNS 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.

DRUG INTERACTIONS:       
Combined use of fluoxetine and MAO inhibitors is contraindicated (see Contraindications).

There have been greater than 2-fold increases of previously stable plasma levels of other antidepressants when fluoxetine has been administered in combination with these agents.

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.

Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness and gastrointestinal distress.

The half-life of concurrently administered diazepam may be prolonged in some patients. Experience with the use of fluoxetine in combination with other CNS-active drugs is limited and caution is advised if such concomitant medication is required (see Warnings).

Drugs Tightly Bound to Plasma Protein:
Because fluoxetine is highly bound to plasma protein, the administration of fluoxetine to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound fluoxetine by other tightly bound drugs.

P450 isozyme (IID6):
Like other selective serotonin reuptake inhibitors, fluoxetine inhibits the specific hepatic cytochrome P450 isozyme (IID6) which is responsible for the metabolism of debrisoquine and sparteine. Although the clinical significance of this effect has not been established, inhibition of IID6 may lead to elevated plasma levels of co-administered drugs which are metabolized by this isozyme. Drugs metabolized by cytochrome P450IID6 include the tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g., perphenazine and thioridazine), and Type 1C antiarrhythmics (e.g., propafenone and flecainide).

General Anesthetics:
Since little is known about the interaction between fluoxetine and general anesthetics, fluoxetine should be discontinued for as long as clinically possible prior to elective surgery.

Dependence Liability:
Fluoxetine 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 fluoxetine.

OVERDOSE:           
During clinical trials, there were 2 deaths among approximately 38 reports of acute overdose with fluoxetine, either alone or in combination with other drugs and/or alcohol. One death involved a combined overdose with approximately 1800 mg of fluoxetine and an undetermined amount of maprotiline. Plasma concentrations of fluoxetine and maprotiline were 4.57 mg/L and 4.18 mg/L, respectively.

A second death involved 3 drugs yielding plasma concentrations as follows: Fluoxetine, 1.93 mg/L; norfluoxetine, 1.10 mg/L; codeine, 1.80 mg/L; temazepam 3.80 mg/L.

One other patient who reportedly took up to 3000 mg of fluoxetine experienced 2 grand mal seizures that remitted spontaneously without specific treatment. Since vomiting occurred, the amount of drug absorbed may have been less than that ingested.

In the postmarketing phase, there have been 16 confirmed reports of overdose of fluoxetine taken alone. The amount of drug ingested has varied from 80 mg to 2000 mg and the patients have ranged in age from 13 to 51 years. There have been no deaths in this group of patients, some of whom were treated vigorously with activated charcoal in the acute phase. Furthermore, patient recoveries were remarkable in the absence of serious adverse events with the exception of a 13 year old male who ingested 1880 mg and experienced 2 brief seizures but thereafter had an uneventful recovery.

Since introduction, reports of death attributed to overdose of fluoxetine alone have been rare.

Symptoms:
Nausea and vomiting were prominent in overdoses involving higher fluoxetine doses. Other prominent symptoms of overdose included agitation, restlessness, hypomania, and other signs of CNS excitation, including seizures.

Treatment:
Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose.

Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures. Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures which fail to remit spontaneously may respond to diazepam.

There are no specific antidotes for fluoxetine.

Due to the large volume of distribution of fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre on the treatment of any overdosage.