pms-Fluoxetine Special Precautions

General: Potential Association with Behavioural and Emotional Changes, Including Self-Harm: Pediatrics - Placebo-Controlled Clinical Trial Data: Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer anti-depressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.
Adults and Pediatrics - Additional data: There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.
An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo.
Families and caregivers of patients being treated with pms-FLUOXETINE should be alerted about the need to monitor patients for the emergence of agitation, anxiety, panic attacks, hostility, irritability, hypomania or mania, unusual changes in behaviour, and other symptoms, as well as the emergence of suicidality particularly within several weeks of starting treatment or changing the dose. Such symptoms should be reported immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Discontinuation Symptoms: Patients currently taking SSRIs or newer anti-depressants should NOT be discontinued abruptly, due to risk of discontinuation symptoms. Fluoxetine has only rarely been associated with such symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation, except for fluoxetine, is recommended. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy which makes dose tapering unnecessary in most patients taking this drug (see Dosing Considerations: Discontinuation of Treatment under Dosage & Administration; Dependence as follows; Adverse Events Leading to Discontinuation of Treatment: Adverse Events Subsequent to Discontinuation under Adverse 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: Pharmacokinetics: Accumulation and Slow Elimination under Actions; Dosing Considerations: Discontinuation of Treatment under 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 fluoxetine.
Weight Change: Significant weight loss, especially in underweight depressed patients and the elderly, may be an undesirable result of treatment with fluoxetine. pms-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.
Psychomotor Impairment: 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.
Allergic Reactions (Rash and Accompanying Events): During premarketing testing, 7% of 10 782 patients developed various types of rashes and/or urticaria. Among these cases, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with these allergic reactions include rash, fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely.
In premarketing clinical trials two patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other severe desquamation that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic manifestations suggestive of serum sickness.
Since the introduction of fluoxetine, systemic events, possibly related to vasculitis, and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events.
Anaphylactoid events, including bronchospasm, angioedema, laryngospasm and urticaria alone and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, pms-FLUOXETINE should be discontinued. Particular caution should be exercised in patients with a history of allergic reactions.
Potential for reduced efficacy of tamoxifen with concomitant SSRI use, including fluoxetine: The antitumor agent tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 can lead to reduced plasma concentrations of a primary active metabolite (endoxifen). Chronic use of CYP2D6 inhibitors, including certain SSRIs, together with tamoxifen can lead to persistent reduction in levels of endoxifen (see also Drug-Drug Interactions: Tamoxifen under Interactions). Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. When tamoxifen is used for the treatment of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
Bone Fracture Risk: Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with pms-FLUOXETINE. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs/SNRIs, including fluoxetine, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.
Carcinogenesis and Mutagenesis: For animal data, see Pharmacology: Toxicology: Subchronic/Chronic/Carcinogenicity and Related Toxicity Studies: Carcinogenicity Studies and Mutagenicity Studies under Actions.
Cardiovascular: Fluoxetine is associated with a risk of QTc interval prolongation (see Pharmacology: Pharmacodynamics: Electrocardiography under Actions; Clinical Trial Adverse Drug Reactions: Adults: ECG Findings under Adverse Reactions; Drug-Drug Interactions: QTc-Prolonging Drugs under Interactions). Rare events of torsade de pointes, ventricular fibrillation, cardiac arrest, and sudden death have been reported with fluoxetine during post-market use (see Post-Market Adverse Drug Reactions under Adverse Reactions). If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
pms-FLUOXETINE should be used with caution in patients with conditions such as congenital long QT syndrome and acquired long QT syndrome (e.g. due to concomitant use of a drug that prolongs the QT); a family history of QT prolongation; or other clinical conditions that predispose to arrhythmias (e.g. hypokalemia or hypomagnesemia or hypocalcaemia) or increased exposure to fluoxetine (e.g. hepatic impairment). Electrocardiogram monitoring may be warranted in patients who are suspected to be at an increased risk of experiencing torsade de pointes, such as cardiac disease (e.g. ischemic heart disease, congestive heart failure, history of arrhythmias), a family history of QT prolongation, recent myocardial infarction, bradyarrhythmias, patients on concomitant medications that prolong the QTc interval or other clinical conditions that predispose to arrhythmias (e.g. acute neurological events, diabetes mellitus, autonomic neuropathy). Female gender and age 65 years or older are risk factors for torsade de pointes.
When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.
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. The mean heart rate was reduced by approximately 3 beats/minute.
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 and at regular intervals thereafter.
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.
Dependence: Discontinuation of Treatment with Fluoxetine (Post-Marketing and Clinical Trials): When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia or other symptoms which may be of clinical significance).
Fluoxetine has been only rarely associated with such symptoms. Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dose tapering unnecessary in most patients (see Dosing Considerations: Discontinuation of Treatment under Dosage & Administration; General: Potential Association with Behavioural and Emotional Changes, Including Self-Harm: Discontinuation Symptoms as previously mentioned; Adverse Events Leading to Discontinuation of Treatment: Adverse Events Subsequent to Discontinuation under Adverse Reactions).
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 pms-FLUOXETINE.
Endocrine and Metabolism: Diabetes: 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.
Hematologic: Abnormal Bleeding: SSRIs and SNRIs, including pms-FLUOXETINE , may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of pms-FLUOXETINE and NSAIDs, ASA, or other drugs that affect coagulation (see Drug-Drug Interactions: Drugs Affecting Platelet Function (e.g. NSAIDs, ASA and other anticoagulants) under Interactions). Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g. thrombocytopenia).
Hepatic/Biliary/Pancreatic: Hepatic Impairment: Since clearances of fluoxetine and norfluoxetine may be decreased in patients with impaired liver function including cirrhosis, a lower or less frequent dose should be used in such patients. See Pharmacology: Pharmacokinetics: Special Populations and Conditions: Hepatic Insufficiency under Actions.
Neurologic: Seizures: pms-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.
Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, including fluoxetine, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with pms-FLUOXETINE should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome, pms-FLUOXETINE should not be used in combination with MAO inhibitors (including the antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs) or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John's Wort) due to the risk of serotonergic syndrome (see Monoamine Oxidase Inhibitors under Contraindications; Drug-Drug Interactions: Monoamine Oxidase Inhibitors and Serotonergic Drugs under Interactions).
Ophthalmologic: Angle-Closure Glaucoma: As with other antidepressants, pms-FLUOXETINE can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.
Psychiatric: Suicide risk: The possibility of a suicide attempt is inherent in depression and other psychiatric disorders and may persist until significant remission occurs. As with other drugs with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during fluoxetine therapy or early after treatment discontinuation.
Although a causal role for fluoxetine in inducing such events has not been established, an FDA analysis from pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviours in pediatric and young adult (<25 years of age) patients compared to placebo.
Close supervision of high-risk patients should accompany drug therapy and consideration should be given to the possible need for hospitalization. Physicians should encourage patients of all ages to report any new or worsened distressing thoughts or feelings occurring at any time. In order to minimize the opportunity for overdosage, prescriptions for fluoxetine should be written for the smallest quantity of drug consistent with good patient management.
Because of the well-established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see General: Potential Association with Behavioural and Emotional Changes, Including Self-Harm as previously mentioned).
Activation of Mania/Hypomania: During premarketing clinical trials in a patient population comprised primarily of unipolar depressed patients, hypomania or mania occurred in approximately 1% of fluoxetine treated patients. The incidence in a general patient population which might also include bipolar depressives is unknown. The likelihood of hypomanic or manic episodes may be increased at the higher dosage levels. Such reactions require a reduction in dosage or discontinuation of the drug.
A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.
Electroconvulsive Therapy (ECT): There are no clinical studies to support the safety and efficacy of combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Renal: Severe Renal Impairment: 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.
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.
In two 6-week controlled studies in patients ≥60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo recipients had a lowering of serum sodium below the reference range; this difference was not statistically significant. The lowest observed concentration of sodium in a fluoxetine treated patient was 129 mmol/L. The observed decreases were not clinically significant.
Male Fertility: Animal data have shown that fluoxetine at levels in excess of the maximum tolerable dose may affect sperm quality (see Pharmacology: Toxicology: Subchronic/Chronic/Carcinogenicity and Related Toxicity Studies: Subchronic Toxicity Studies and Reproductive and Impairment of Fertility Studies under Actions). In human case reports, some reversible changes in sperm quality have been reported with some SSRIs, including fluoxetine. An impact on human fertility has not been observed.
Use in Children: pms-FLUOXETINE is not indicated for use in patients below the age of 18 years. See General: Potential Association with Behavioural and Emotional Changes, Including Self-Harm as previously mentioned. See also Clinical Trial Adverse Drug Reactions: Special Populations: Pediatrics (<18 years of age): Potential for Effects on Growth in Pediatric Patients under Adverse Reactions.
Use in 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. See Geriatrics (≥60 years of age) under Indications/Uses; Special Patient Populations: Use in the Elderly under Dosage & Administration.