Fluoxetine Adverse Reactions
- acneiform rash
- agitation
- akathisia
- alopecia
- amnesia
- anemia
- angioedema
- anorexia
- anxiety
- back pain
- bleeding
- blurred vision
- bronchospasm
- chills
- confusion
- contact dermatitis
- cough
- diaphoresis
- diarrhea
- dizziness
- drowsiness
- dysgeusia
- dyspepsia
- dyspnea
- dystonic reaction
- ejaculation dysfunction
- emotional lability
- epistaxis
- erythema nodosum
- exfoliative dermatitis
- fatigue
- growth inhibition
- headache
- hot flashes
- hyperglycemia
- hypertension
- hypoglycemia
- hyponatremia
- hypothyroidism
- impotence
- increased urinary frequency
- infection
- insomnia
- laryngospasm
- libido decrease
- lupus-like symptoms
- maculopapular rash
- mania
- menorrhagia
- myalgia
- nasal congestion
- nausea/vomiting
- orgasm dysfunction
- orthostatic hypotension
- palpitations
- pharyngitis
- platelet dysfunction
- priapism
- pruritus
- rash (unspecified)
- seizures
- serotonin syndrome
- serum sickness
- SIADH
- sinus bradycardia
- sinusitis
- Stevens-Johnson syndrome
- suicidal ideation
- torticollis
- toxic epidermal necrolysis
- tremor
- urticaria
- vasculitis
- visual impairment
- weight gain
- weight loss
- withdrawal
- xerosis
- xerostomia
- yawning
Fluoxetine Adverse Reactions
In general, most adverse events reported with fluoxetine are similar between adult and pediatric populations. The safety of fluoxetine for treatment periods longer than several months has not been assessed in pediatric patients. Pediatric-specific events that have not been reported in adults and that occur at an incidence greater than 2% (and at an incidence greater than that of placebo) include: hyperkinesia, personality disorder, epistaxis, and menorrhagia.
Adverse CNS reactions can occur in patients receiving fluoxetine and include anxiety, nervousness, insomnia, drowsiness, fatigue, dizziness, tremor, and headache. Headache is the most commonly reported CNS effect. Some CNS effects can diminish with therapy because they are associated with a depressed state. In severe cases, discontinuation of the drug may be necessary. Sedation is generally less of a problem with fluoxetine than with tricyclic antidepressants, but patients should exercise caution during activities requiring mental alertness until the effects of the drug are known. According to the manufacturer’s product literature, drowsiness occurred in 11.6% while a ‘sedated’ feeling occurred in 1.9%. Many of these CNS adverse effects have been reported in the manufacturer’s labeling as occurring during abrupt discontinuation of fluoxetine (specifically with Sarafem®).
All effective antidepressants can transform depression into mania in predisposed individuals. In US clinical trials for depression, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. In clinical trials for obsessive-compulsive disorder, mania/hypomania was reported in 0.8% of fluoxetine-treated patients and in no patients treated with placebo. If mania occurs, the antidepressant should be held and appropriate therapy to treat the manic symptoms initiated. Mania/hypomania was reported in 2.6% of pediatric patients receiving fluoxetine in clinical trials, and was the most common reason for discontinuation from studies (1.8%). Pediatric placebo-controlled groups reported 0% discontinuation due to mania/hypomania.
Fluoxetine can cause drug-induced seizures, but has been reported at a very low frequency (12 of 6,000 patients). This reaction is likely to occur only following overdose, after long-term therapy, or in the presence of a preexisting seizure disorder. Neonates exposed to SSRIs or SNRIs, late in the third trimester have also rarely developed seizures as part of a drug discontinuation syndrome.
Suicidal ideation has been reported in antidepressant clinical trials. The symptoms of aggressiveness, akathisia (psychomotor restlessness), agitation, anxiety, insomnia, irritability, hostility, mania, hypomania, impulsivity, and panic attacks have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidal ideation. A change or discontinuation of the therapeutic regimen should especially be considered if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Many of these adverse symptoms have been reported in clinical trials and have not always been associated with suicidality. For example, rare extrapyramidal symptoms (dystonia, torticollis, akathisia or other dystonic reaction) have occurred in some patients taking fluoxetine. Akathisia is the most commonly observed of these adverse reactions and is easily confused with anxiety or agitation. Rapid discontinuation of SSRIs may also result in many of these adverse CNS events.
Nausea/vomiting is the most common (incidence roughly 20%) adverse reaction to fluoxetine. Nausea usually subsides after a few weeks of therapy but occasionally is severe enough to necessitate discontinuation of the drug. Nausea occurs more frequently with fluoxetine than with tricyclic antidepressant drugs. Diarrhea, anorexia, xerostomia, and dyspepsia are also fairly common (~10%) and may require medical attention. Anorexia can result from serotonin-reuptake blockade, and tolerance to this effect does not appear to occur. Weight loss exceeding 5% of body weight has been reported in 10-15% of fluoxetine-treated patients. Higher doses are correlated with higher weight loss. Approximately 1% of patients require discontinuation due to this adverse effect. Underweight patients should have their weights monitored weekly to prevent further weight loss. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction.
Hypoglycemia has been observed rarely in patients treated with fluoxetine. Hyperglycemia has been observed following discontinuation of fluoxetine. Patients with diabetes mellitus should be monitored closely during initiation or discontinuation of fluoxetine.
Visual impairment, including blurred vision, occurs in about 3% of patients receiving fluoxetine.
Fluoxetine is substantially less cardiotoxic than are the tricyclic antidepressants. Sinus bradycardia, consisting of a decrease of 3 beats/minute, has been reported in patients taking fluoxetine. Orthostatic hypotension occurs in fewer than 1% of patients. Palpitations, hot flashes, and angina have been reported infrequently.
Myalgia and/or joint, limb, or back pain occurs in 1-2% of patients receiving fluoxetine.
Anemia has been reported in fewer than 1% of patients receiving fluoxetine. Bleeding has also been reported during fluoxetine therapy but this appears to be an extremely rare event. It appears that fluoxetine may directly affect hemostasis, perhaps by affecting platelet aggregation (i.e., platelet dysfunction).
Upper respiratory infection (URI) has been observed in 8% of patients treated with fluoxetine. Other respiratory effects that have been reported in 1-3% of fluoxetine treated patients include yawning, pharyngitis, nasal congestion, sinusitis, sinus headache, cough, and dyspnea.
Sexual dysfunction including ejaculation dysfunction (delayed ejaculation), impotence, orgasm dysfunction (anorgasmia, spontaneous or delayed orgasm), libido decrease, and penile anesthesia were reported in roughly 2% of patients receiving fluoxetine during initial clinical trials. Although the manufacturer reports that sexual dysfunction occurs in 1.9% of patients, some believe that it may occur in as many as 75% of patients. Priapism has been reported rarely with all of the SSRIs. Post-marketing experience has suggested that the frequency of sexual adverse events is actually much higher than previously recognized. The FDA is considering changing the labeling of SSRIs to reflect a higher frequency of drug-induced sexual adverse events.
Fluoxetine can cause a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that presents as hyposmolarity of serum and urine, and hyponatremia. Older patients and those receiving diuretics appear to be more at risk. Increased urinary frequency occurs in 2% of patients receiving fluoxetine.
Hypothyroidism is reported in ~1% of patients receiving fluoxetine, although a causal relationship to fluoxetine therapy has not been established. Even slight hypothyroidism (thyroid-stimulating hormone (TSH) >= 3) can prevent response to antidepressant therapy.
Pruritus and rash (unspecified) occur during the first few weeks of therapy in 2-4% of patients receiving fluoxetine. Diaphoresis occurs in roughly 10% of patients. Only 1% of patients require discontinuation of fluoxetine due to allergic reactions. All dermatological reactions should be investigated because they could be precursors of a serious systemic reaction to the drug. In most cases, maculopapular rash or urticaria disappears with treatment with an antihistamine or corticosteroid, or upon discontinuation of the drug. Other dermatologic reactions occurring in <1% of patients include alopecia, acneiform rash, contact dermatitis, erythema nodosum, and xerosis. Patients have had systemic syndromes suggestive of serum sickness. Since the introduction of fluoxetine, systemic events, possibly related to vasculitis and including lupus-like symptoms, 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 reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Serious skin reactions, like exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported in post-market voluntary reporting. Pulmonary events, including inflammatory processes of varying histopathology and/or pulmonary 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 is not known; a specific underlying immunologic basis for these events has not been identified. If allergic phenomena occur for which an alternative etiology cannot be identified, fluoxetine should be discontinued.
The following adverse events have also been reported to occur in 1% of fluoxetine-treated patients for all indications, except those already listed. These events come from data in all trials, including open-label and uncontrolled studies. Some events occurred at rates similar to placebo in controlled clinical trials. The following events are listed by body system. Body as a whole: chills (without concurrent fever). Cardiovascular system: hemorrhage, hypertension. Central nervous system: agitation, amnesia, confusion, emotional lability, and sleep disorder (undefined). Gastrointestinal: increased appetite, nausea with vomiting. Metabolic/nutritional: weight gain. Special senses: otalgia, taste perversion (dysgeusia), tinnitus. Urogenital: increased urinary frequency. NOTE; additional reported infrequent side effects (0.1-1% of patients) and rare events (<= 0.1% of patients) in which a causal relationship to fluoxetine has not been established are listed in the manufacturer’s prescribing information.
From 1989 through 1995, 228 women taking fluoxetine during pregnancy were prospectively evaluated. Although the rate of spontaneous pregnancy loss or major structural anomalies was not significantly different from women not taking fluoxetine, there was a higher incidence of infants with 3 or more minor anomalies. Seventy-three infants exposed to fluoxetine during the third trimester had a higher rate of premature delivery, poorer neonatal adaptation, lower birth weight, and shorter birth length than 101 infants exposed only during the first or second trimesters.
Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential withdrawal symptoms. However, fluoxetine is a long-acting SSRI, and withdrawal symptoms are uncommon due to the long half-life of the drug’s active metabolite. Withdrawal symptoms have been reported with abrupt or rapid discontinuation of fluoxetine (Sarafem®) including dysphoric mood, irritability, agitation, dizziness, paresthesias, headache, hypomania, anxiety, confusion, lethargy, emotional lability and insomnia. The most commonly reported SSRI withdrawal symptoms include fatigue, abdominal pain or nausea, dizziness/light-headedness, tremor, chills, diaphoresis, and incoordination. Withdrawal symptoms usually begin 1-3 days after abrupt discontinuation of the short-acting SSRI and remit within 1-2 weeks; although with fluoxetine this may be delayed due to the long half-life of the active metabolite. The difference in the incidence of withdrawal symptoms among SSRIs is most likely due to differences in the half-lives of the active moieties.
Serotonin syndrome has been reported when SSRIs are administered concomitantly with other medications known to increase CNS or peripheral serotonin levels or during SSRI overdose. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. This is probably most frequently reported with fluoxetine. Symptoms may include nausea, vomiting, sedation, dizziness, diaphoresis (sweating), facial flush, mental status changes, myoclonia, restlessness, shivering, and hypertension. Fluoxetine exhibits a prolonged half-life due to the active metabolite that warrants consideration in such cases. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. Other important adverse events reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like events, pyrexia, stupor, and syncope. Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
In one fluoxetine clinical trial at 19 weeks, children and adolescents 8-17 years gained about 1.1 cm less in height and about 1 kg less in weight compared to pediatric patients treated with placebo. Although these differences were statistically significant, the clinical significance of this observation on long-term growth is not known. Further studies are underway to evaluate the impact of fluoxetine on growth or if the use of SSRIs may result in growth inhibition. The mechanism in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.
[ Last revised: 11/9/2005 6:25:00 PM ]
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