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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 Among these cases, almost a third were withdrawn from the treatment because of the rash and/or systemic signs or symptoms associated with the rash.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 vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness.
Since the introduction of fluoxetine, systemic events, possible related to vasculitis, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver.
Anaphylactoid events, including bronchospasm, angioedema and urticaria along 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 other possible allergic phenomena for which an alternative etiology cannot be identified, APO-FLUOXETINE (fluoxetine hydrochloride) 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 nor-fluoxetine, 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 Actions and Dosage & 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 APO-FLUOXETINE.
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 APO-FLUOXETINE (fluoxetine hydrochloride).
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 hypomania or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.
Seizures: APO-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 prolonged seizures in patients on fluoxetine receiving ECT treatment.
Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.
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 hydrochloride 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 diagnosis were systemically excluded from premarketing clinical studies. Retrospective evaluation of EKG's 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.
APO-FLUOXETINE should be given with caution to patients suffering from anorexia 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 concurrent 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 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.
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 possible due to the syndrome of inappropriate antidiuretics 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.
Cognitive and Motor Performance: Patients should be cautioned against driving an automobile or performing hazardous tasks until they are reasonably certain that treatment with APO-FLUOXETINE does not affect them adversely.
Use in Pregnancy & 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 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 as 295.0 ng/mL. No adverse effects on the infant were reported.
Use in Children: Safety and effectiveness in patients below the age of 18 have not been established.
Use in the Elderly: Evaluation of patients over the age of 60 who received fluoxetine 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.
