Adverse Drug Reaction Overview: Commonly Observed Adverse Events:
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: central nervous system complaints, including headache, nervousness, insomnia, drowsiness, fatigue or asthenia, anxiety, tremor, and dizziness or light-headedness; gastrointestinal complaints, including nausea, diarrhea, dry mouth and anorexia; and excessive sweating.
Adverse Events Leading to Discontinuation of Treatment:
Fifteen percent of approximately 4,000 patients who received fluoxetine in North American clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation from depression trials in adults and elderly, included: psychiatric, primarily nervousness, anxiety, and insomnia; digestive, primarily nausea; nervous system, primarily dizziness, asthenia, and headaches; skin, primarily rash and pruritus.
In obsessive compulsive disorder studies, 12.1% of fluoxetine treated patients discontinued treatment early because of adverse events. Anxiety and rash, at incidences of less than 2%, were the most frequently reported events. In bulimia nervosa studies, 10.2% of fluoxetine treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidences of less than 2%, were the most frequently reported events.
Adverse Events Subsequent to Discontinuation:
Symptoms associated with discontinuation of fluoxetine have been reported in clinical trials and post-marketing (e.g. headache, insomnia, paresthesias, nervousness, anxiety, nausea, sweating, numbness, dizziness, jitteriness, asthenia, or other symptoms which may be of clinical significance). The majority of these are mild and self-limiting. 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 under Precautions.
Serious Adverse Reactions:
Suicidal thoughts and acts are far more common among depressed patients than in the general population. It is estimated that suicide is 22 to 36 times more prevalent in depressed persons than in the general population. A comprehensive meta-analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder compared fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants.
In countries where the drug has already been marketed, the following potentially serious adverse reactions have been reported; interactions with MAO inhibitors and possibly other drugs, allergic reactions, cardiovascular reactions, syndrome of inappropriate ADH secretion, and grand mal seizure. Death and life-threatening events have been associated with some of these reactions, although causal relationship to fluoxetine has not necessarily been established.
Post-marketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with fluoxetine including allergic skin reactions.
Clinical Trial Adverse Drug Reactions:
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Multiple doses of fluoxetine had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories.
In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. (See Table 4.)
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Table 5 enumerates treatment-emergent adverse events that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in US controlled clinical trials comparing fluoxetine with placebo in the treatment of depression, OCD, or bulimia. Table 5 provides combined data for the pool of studies that are provided separately by indication in Table 4. (See Table 5.)
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Table 6 lists the adverse events associated with discontinuation of fluoxetine treatment (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary event associated with discontinuation) in depression, OCD, and bulimia. For symptoms associated with discontinuation of fluoxetine in clinical trials and post-marketing, see Post-Market Adverse Drug Reactions as follows. (See Table 6.)
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Male and Female Sexual Dysfunction with SSRIs:
Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in depression, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia.
There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Symptoms of sexual dysfunction occasionally persisting after discontinuation of fluoxetine treatment have been observed in spontaneous reports. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Treatment-Emergent Adverse Events:
Following is a list of all treatment-emergent adverse events reported at any time by individuals taking fluoxetine in US clinical trials (10 782 patients) except: (1) those listed in the body or footnotes of Tables 4 or 5 or elsewhere in monograph; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to fluoxetine use was considered remote; and (4) events occurring in only 1 patient treated with fluoxetine and which did not have a substantial probability of being acutely life-threatening.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 but at least 1/1000 patients; rare events are those occurring in less than 1/1000 patients.
Body as a Whole: Frequent: chills.
Infrequent: chills and fever, face edema, feeling abnormal, intentional overdose, malaise, pelvic pain, suicide attempt.
Rare: abdominal syndrome acute, hypothermia, intentional injury, neuroleptic malignant syndrome‡
, photosensitivity reaction.
*characterized by the clustering of clinical features of changes in mental state and neuromuscular activity, in combination with autonomic nervous system dysfunction.
Cardiovascular System: Frequent: hemorrhage, hypertension.
Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache.
Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.
Digestive System: Frequent: increased appetite, nausea and vomiting.
Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst.
Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, oesophageal pain, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.
Endocrine System: Infrequent: hypothyroidism.
Rare: diabetic acidosis, diabetes mellitus.
Hemic and Lymphatic System: Infrequent: anemia, ecchymosis.
Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia.
Metabolic and Nutritional: Frequent: weight gain.
Infrequent: dehydration, generalized edema, gout, hypercholesterolemia, hyperlipemia, hypokalemia, peripheral edema.
Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcaemia, iron deficiency anemia, SGPT increased.
Musculoskeletal System: Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis.
Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.
Nervous System: Frequent: abnormal movement/tremor1
, agitation, amnesia, confusion, emotional lability, fatigue2
, headache, sleep abnormalities3
Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, balance disorder, bruxism, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder†
, psychosis, vertigo.
Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor.
Respiratory System: Infrequent: asthma, epistaxis, hiccup, hyperventilation.
Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.
Skin and Appendages: Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discolouration, skin ulcer, vesiculobullous rash.
Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea.
Special Senses: Frequent: ear pain, taste perversion, tinnitus.
Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia.
Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.
Urogenital System: Frequent: gynaecological bleeding*, sexual dysfunction*,4
, urinary frequency.
Infrequent: abortion*, albuminuria, amenorrhea*, breast enlargement, breast pain, cystitis, dysuria, female lactation*, fibrocystic breast*, hematuria, leukorrhea*, menorrhagia*, metrorrhagia*, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency.
Rare: breast engorgement, glycosuria, hypomenorrhea*, kidney pain, oliguria, priapism*, uterine fibroids enlarged*.
In a placebo-controlled clinical trial in major depressive disorder, fluoxetine titrated to doses in the range of 40-80 mg/day was associated with a statistically significant placebo-adjusted mean change from baseline in the Fridericia-corrected QT interval (QTcF=QT/RR0.33
) of 8.6 ms (90% CI 4.5, 12.6). See Pharmacology: Pharmacodynamics: Electrocardiography under Actions; Cardiovascular under Precautions; Drug-Drug Interactions: QTc-Prolonging Drugs under Interactions.
(only Adverse Events that are different from the previously mentioned events are listed under Special Populations.)
Pediatrics (<18 years of age):
Potential for Effects on Growth in Pediatric Patients: 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 under Precautions).
Decreased weight gain and a lesser gain in height have been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine (n = 88) were recorded as gaining an average of 1.1 cm less in height than subjects treated with placebo (n = 75). However, the study was not designed for a rigorous assessment of growth (e.g. heights were recorded to the nearest rounded inch), and thus a definite interpretation of this finding was compromised. This is exemplified by the reported outcome of a loss in height for 17 of the patients. Notwithstanding these limitations, an attenuation of height gain with acute fluoxetine treatment cannot be excluded. (See also Pharmacology: Toxicology: Subchronic/Chronic/Carcinogenicity and Related Toxicity Studies: Juvenile Toxicology Study under Actions.) Fluoxetine treatment was also associated with a decrease in serum alkaline phosphatase levels in this study. 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.
Post-Market Adverse Drug Reactions:
Voluntary reports of adverse events temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, bone fractures, cardiac arrest, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gastrointestinal bleeding5
, galactorrhea, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of pre-existing movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in most severe cases, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias and ventricular fibrillation) and violent behaviours.
Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome.
COSTART group term abnormal movement/tremor includes the independent terms: frequent: tremor; infrequent: ataxia, buccoglossal, myoclonus; rare: twitching.
COSTART group term fatigue includes the independent terms: frequent: asthenia, somnolence.
COSTART group term sleep abnormalities includes the independent terms: frequent: insomnia; rare: abnormal dreams.
Personality disorder is the COSTART term for designating non-aggressive objectionable behaviour.
* Adjusted for gender.
COSTART group term sexual dysfunction includes the independent terms: frequent: impotence, libido decreased; infrequent: anorgasmia, delayed or absent ejaculation.
Includes: esophageal varices hemorrhage, gingival and mouth bleeding, hematemesis, hematochezia, hematomas [intraabdominal, peritoneal], hemorrhage [anal, esophageal, gastric, gastrointestinal (upper and lower), haemorrhoidal, peritoneal, rectal], hemorrhagic diarrhoea and enterocolitis, hemorrhagic diverticulitis, hemorrhagic gastritis, melaena, and ulcer hemorrhage [esophageal, gastric, duodenal].