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 lightheadedness; 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 rceived 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 rash and pruritis.
In obsessive compulsive disorder studies, 12.1% of fluoxetine-treated patients discontinue treatment early because of adverse events. In bulimia nervosa studies, 10.2% of fluoxetine-treated patients discontinued treatment early because of adverse events. Insomnia, anxiety and rash, at incidence of less than 2%, were the most frequently-reported events.
Serious Adverse Reactions:
Suicidal thoughts and acts are 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 date 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 casual relationship to fluoxetine has not necessarily been established.
Postmarketing experience also confirms the profile of adverse reactions commonly reported during clinical trials with fluoxetine hydrochloride including allergic skin reactions.
Adverse Experience Reports:
The pattern of treatment-emergent adverse experience incidence (>5%) for both fluoxetine and placebo was somewhat different in bulimia and obessive compulsive disorder trials than in the adult and elderly depression studies, and is summarized in the following table. (See Table 3.)
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The following adverse reactions were reported on at least one occasion by patients during treatment with fluoxetine either during clinical trials or after marketing. All reported events are included except those where a drug cause was remote or the event term so general as to be unhelpful. Multiple events may have been reported by a single condition, which may have preexisted. Therefore, while the following events occurred during treatment with fluoxetine, they were not necessarily caused by it.
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.
Allergic or Toxic:
Frequent: rash, pruritis.
Infrequent: chills and fever, urticaria, maculopapular rash.
Rare: allergic reactions, erythema multiforme, vesiculobullous rash, serum sickness, contact dermatitis, erythema nodosum, purpuric rash, leukocytoclastic vasculitis, leukopenia, thrombocytopenia, arthralgia, angioedema, bronchospasm, lung fibrosis, allergic alveolitis, larynx edema, respiratory distress.
Frequent: headache, tremor, dizziness or lightheadedness, asthenia.
Infrequent: abnormal gait, ataxia, akathisia, buccoglossal syndrome, hyperkinesia, hypertonia, incoordination, neck rigidity, extrapyramidal syndrome, convulsions, photophobia, myoclonus, vertigo, migraine, tinnitus, hyperthesia, neuralgia, neupathy, acute brain syndrome.
Rare: dysarthria, dystonia, torticollis, decreased reflexes, nystagmus, paralysis, paresthesia, carpal tunnel syndrome, stupor, coma, abnormal electroencephalogram, chronic brain syndrome, dyskinesia and other movement disorders (including worsening of preexisting conditions or appearance in patients with risk factors [e.g. Parkinson's disease, treatment with neuroleptics or other drugs known to be associated with movement disorders]), neuroleptic malignant syndrome-like events.
Frequent: insomnia, anxiety, nervousness, agitation, abnormal dreams, drowsiness and fatigue.
Infrequent: confusion, delusions, hallucinations, manic reaction, paranoid reaction, psychosis, depersonalization, apathy, emotional liability, euphoria, hostility, amnesia, increased libido.
Rare: antisocial reaction, hysteria, suicidal ideation, violent beaviours.
Frequent: excessive sweating.
Infrequent: dry mouth, constipation, urinary retention, vision disturbance, diplopia, mydriasis, hot flushes.
Infrequent: chest pain, hypertension, syncope, hypotension (including postural hypotension), angina pectoris, arrhythmia, tachycardia.
Rare: bradycardia, ventricular arrhythmia, first degree AV block, bundle branch block, myocardial infarction, cerebral ischemia, cerebral vascular accident, thrombophlebitis.
Frequent: nausea, disturbance of appetite, diarrhea.
Infrequent: vomiting, stomatitis, dysphagia, eructation, esophagitis, duodenal ulcer, stomach ulcer, mouth ulceration, hyperchlorhydria, colitis, enteritis, cholocystitis, cholelithiasis, hepatitis, hepatomegaly, liver tenderness, jaundice, increased salivation, saliva gland enlargement, tongue discolouration, fecal incontinence, pancreatitis.
Frequent: bronchitis, rhinitis, yawn.
Infrequent: asthma, dyspnea, hyperventilation, pneumonia, hiccups, epistaxis.
Rare: apnea, lung edema, hypoxia, pleural effusion, hemoptysis.
Frequent: weight loss.
Infrequent: generalized edema, peripheral edema, face edema, tongue edema, hypoglycemia, hypothyroidism, weight gain.
Rare: dehydration, gout, goitre, hyperthyroidism, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperprolactinemia, hypokalemia, hyponatremia, iron deficiency anemia, syndrome of inappropriate ADH pancytopenia, immune-related hemolytic anemia.
Infrequent: acne, alopecia, dry skin, herpes simplex.
Rare: eczema, psoriasis, seborrhea, skin hypertrophy, skin discolouration, herpes zoster, fungal dermatitis, hirsutism, ecchymoses.
Frequent: muscle pain, back pain, joint pain.
Infrequent: arthritis, bone pain, bursitis, tenosynovitis, twitching.
Rare: bone necrosis, osteoporosis, pathological fracture, chrondrodystrophy, myositis, rheumatoid arthritis, muscle hemorrhage.
Frequent: painful menstruation, sexual dysfunction, urinary tract infection, frequent micturition.
Infrequent: abnormal ejaculation, menopause, amenorrhea, menorhagia, ovarian disorder, vaginitis, leukorrhea, fibrocystic, breast pain, cystitis, dysuria, urinary urgency, urinary incontinence.
Rare: breast enlargement, galactorrhea, abortion, dyspareunia, uterine spasm, vaginal hemorrhage, metorrhagia, hematuria, albuminuria, polyuria, pyuria, epididymitis, orchitis, pyelonephritis, salpingitis, urethritis, kidney calculus, urethral pain , urolithiasis.
Frequent: chills, abnormal vision.
Infrequent: amblyopia, conjunctivitis, cyst, ear pain, eye pain, jaw pain, neck pain, pelvic pain, hangover effect, malaise.
Rare: abdomen, enlarged blepharitis, cataract, corneal lesion, glaucoma, iritis, ptosis, strabismus, deafness, taste loss, moniliasis, hydrocephalus, LE syndrome.