Effexor XR (Venlafaxine) Adverse Reactions
- agitation
- akathisia
- anorexia
- anxiety
- asthenia
- bleeding
- blurred vision
- constipation
- diaphoresis
- dizziness
- drowsiness
- dyskinesia
- ecchymosis
- ejaculation dysfunction
- elevated hepatic enzymes
- hepatitis
- hostility
- hypercholesterolemia
- hypertension
- hyponatremia
- impotence
- insomnia
- irritability
- libido decrease
- mania
- mydriasis
- nausea/vomiting
- neonatal abstinence syndrome
- priapism
- QT prolongation
- rhabdomyolysis
- seizures
- serotonin syndrome
- SIADH
- sinus tachycardia
- suicidal ideation
- tardive dyskinesia
- tremor
- weakness
- weight loss
- withdrawal
- xerostomia
Effexor XR (Venlafaxine) Adverse Reactions
In clinical trials, common CNS adverse events observed with venlafaxine at an incidence >= 5% and twice that of placebo included: drowsiness (23% compared to 9% with placebo), asthenia (weakness) (15 vs. 3%); dizziness (19 vs. 7%), xerostomia (22 vs. 11%), insomnia (18 vs. 10%), nervousness/anxiety (13/6 and 6/3%), and tremor (5 vs. 1%). Xerostomia, asthenia, anxiety, insomnia, nervousness and tremor resulted in discontinuation of therapy for some patients. Over a period of 6 weeks, some patients adapted to the dizziness but not the xerostomia. Although the incidences are too low to determine causality, dyskinesia and tardive dyskinesia have been documented in post-marketing reports with venlafaxine. All effective antidepressants can precipitate mania in predisposed individuals suffering from depression. In premarketing trials, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of placebo-treated patients. If mania occurs, the antidepressant should be held and appropriate therapy to treat the manic symptoms initiated. Suicidal ideation also 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 patients presenting symptoms. Many of these adverse symptoms have been reported in clinical trials and have not always been associated with suicidality. Rapid discontinuation of SSRIs may also result in many of these adverse CNS events.
Venlafaxine can induce a sustained dose-related hypertension (typically 10 - 15 mm Hg). When doses of 100 - 300 mg/day are used the incidence of sustained elevation in blood pressure rises 5 - 7%; when doses > 300 mg/day are prescribed, blood pressure can elevate up to 13% over baseline. Regular monitoring of blood pressure is recommended for all patients. Blood pressure increases may necessitate a dose reduction or possible discontinuation of venlafaxine. In trials, hypertension was recorded in 2.2% of patients receiving venlafaxine doses of 225 (n=89) and 4.5% receiving 375 mg (n=88). Analysis of ECG changes in 769 patients showed statistically significant and dose-related changes in heart rate (relative increase of 4 - 8 beats/min). QT prolongation has been documented with a mean increase in QTc of 4.7 msec vs. a decrease of 1.9 msec for venlafaxine extended-release vs. placebo, respectively. Sinus tachycardia and QT prolongation have also been reported as a result of venlafaxine overdose.
Gastrointestinal (GI) adverse effects of venlafaxine are very common. In trials, nausea/vomiting (37%/6% vs. 11%/2% with placebo), anorexia (11 vs. 2%), constipation (15 vs. 7%), were frequently reported and resulted in venlafaxine discontinuation for some patients. Over several weeks, patients may adapt to the GI effects of venlafaxine. Venlafaxine also leads to a dose-dependent weight loss in some patients. Weight loss occurring with venlafaxine is not always associated with treatment-induced anorexia. In adult major depression disorder (MDD) clinical trials, about 5% of body weight was lost in 7% of patients receiving venlafaxine XR, compared to 2% of patients receiving placebo. The discontinuation rate due to weight loss in depression trials was low, roughly 0.1% of patients. Weight loss in adult general anxiety disorder (GAD) trials (lasting up to 6 months) was similar to the weight loss in depression trials. Weight loss in panic and social anxiety disorder trials was slightly less than that seen in depression and GAD trials. Weight loss has also been noted with pediatric use of venlafaxine. In 8-week studies for MDD or GAD, venlafaxine-treated pediatric patients lost an average of 0.45 kg while placebo-treated patients gained an average of 0.77 kg. Eighteen percent of children in the venlafaxine group lost >= 3.5% of body weight compared to 3.6% of the placebo group, a significant difference. In social anxiety disorder (SAD) studies, pediatric patients lost on average 0.75 kg while placebo groups gained roughly the same amount. Additionally, 47% of venlafaxine-treated children lost >= 3.5% of their body weight compared to 14% of placebo patients. Six month studies in children with MDD have revealed that longer term weight gains are less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children than for adolescents. Changes in height have also been noted in short and long-term studies. In an 8-week study, pediatric patients (ages 6 - 17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); the difference was significant. This difference in height was most notable in patients < 12 years of age.. During a 16-week, placebo-controlled SAD study, both the venlafaxine XR-treated (n = 109) and the placebo-treated (n = 112) patients each grew an average of 1 cm. A six month open-label study also noted height increases that were less than expected based on data from age- and sex-matched peers; however, the long-term consequences are not known. Clinicians should regularly monitor height and weight changes in pediatric patients receiving venlafaxine.
Venlafaxine therapy may cause sexual dysfunction. Libido decrease occurred in 2% of all patients. Ejaculation dysfunction occurred in 12%, impotence in 6%, and orgasm disturbance in 2% of male patients taking part in venlafaxine trials. Priapism has been reported rarely. One percent of female patients reported menstrual disorders.
Other adverse events reported by the manufacturer that required discontinuation of venlafaxine treatment and occurred at an incidence of 5% or greater or twice that of placebo are as follows: blurred vision (6%), sometimes reported as mydriasis; and diaphoresis (12%).
Sudden withdrawal of venlafaxine has produced discontinuation effects including asthenia, dizziness, headache, insomnia, and nervousness in at least 5% of patients, the incidence for venlafaxine being at least twice that for placebo. Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported discontinuation symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. It is therefore recommended that the dosage of venlafaxine be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. When discontinuing venlafaxine after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Patients who have received venlafaxine for more than 6 weeks or more should have their dose tapered gradually over at least a 2-week period. In clinical trials with in patients taking the extended-release product (i.e., Effexor XR® ), tapering was achieved by reducing the daily dose by 75 mg at one week intervals. Individualization of tapering may be necessary. Discontinuation effects are well known to occur with antidepressants. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
In post-marketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram (ECG) changes such as prolongation of QT interval, bundle branch block, QRS prolongation, sinus and ventricular tachycardia, sinus bradycardia have been reported. Other events, such as hypotension, altered level of consciousness (ranging from somnolence to coma), seizures, vertigo, and death have been noted in these reports. The addition of venlafaxine to established clozapine therapy may result in seizure activity (see Drug Interactions). Rapid withdrawal of venlafaxine monotherapy has also been associated with seizures.
In one case report, the initiation of venlafaxine in a patient taking medications known to cause NMS developed symptoms consistent with neuroleptic malignant syndrome (NMS) or serotonin syndrome (NOTE: Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome). Symptoms may include nausea and/or vomiting, sedation, dizziness, diaphoresis (sweating), facial flush, mental status changes, myoclonia, restlessness, shivering, and hypertension. After discontinuation of all psychiatric medications and treatment for NMS, the patient recovered and was able to reinitiate trifluoperazine without further problems. This case report, thought isolated, may signal the need to be cautious in combining venlafaxine with the antipsychotic phenothiazines. Additionally, a withdrawal syndrome that has appeared in newborns of women taking SSRI-type drugs while pregnant has been reported to resemble serotonin syndrome.
Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine and may be a concern for those who are dehydrated, elderly or taking diuretics.
There have been reports, although not causally-related, of abnormal bleeding (primarily ecchymosis) in patients treated with venlafaxine. Impaired platelet aggregation may occur due to platelet serotonin depletion. Elevations in prothrombin time, activated partial thromboplastin and INR values have also been reported post-marketing when venlafaxine was added to established warfarin therapy, although overt bleeding was not reported. The causality and mechanism of this potential interaction have not been established (see Drug Interactions).
Venlafaxine has been associated with clinically important elevations in serum cholesterol (serum cholesterol >= 50 mg/dl from baseline and to a value >= 261 mg/dl) in 5.3% of venlafaxine-treated patients vs. 0% of placebo-treated patients. With at least 3 months of venlafaxine treatment in a 12-month study, the mean elevation in serum cholesterol was 9.1 mg/dl vs. a decrease of 7.1 mg/dl in the placebo group. The increases in serum cholesterol were dose and duration dependent. The manufacturer lists hypercholesterolemia as an infrequent adverse event (occurring in 1/100 to 1/1000 patients). The clinician may wish to monitor serum cholesterol levels at baseline and periodically during treatment with venlafaxine.
Musculoskeletal system disorders, such as rhabdomyolysis, have been documented in spontaneous post-marketing reports with venlafaxine use, but causality cannot be determined due to the low incidence.
A neonatal abstinence syndrome has been reported in infants exposed to serotonergic agents in utero. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) were noted. Such complications can arise immediately upon delivery. Other symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, and constant crying. Serum concentrations of the serotonergic agent were measurable in the infants affected. Several other symptoms (bloody stools, necrotizing enterocolitis) may have been attributable to rebound platelet activation on withdrawal of the exposure to the SSRI. Neonatal symptoms generally improved over several days. Additionally, a cohort study of 55 women revealed that 22% (12/55) of neonates exposed to an SSRI in the third trimester had complications requiring treatment or extended hospitalization compared with 6% in comparison groups. Complications included respiratory distress (n=9), hypoglycemia (n=2) and jaundice (n=1). The incidence of prematurity in the third trimester SSRI group was significant at 20% vs. 3.7% of controls. These features are consistent with either a direct toxic effect of serotonergic agents, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with an SSRI or other serotonergic agent during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, tapering of the serotonergic agent prior to delivery may be considered as an alternative.
Elevated hepatic enzymes (ALT, AST, GGT, and alkaline phosphatase) and probable drug-induced hepatitis were described a case report of a woman aged 60 years who received venlafaxine 75 mg PO daily for vasomotor symptoms. After roughly one month of therapy, the patient presented with abdominal pain and an enlarged liver. Venlafaxine was discontinued, and after 1 week the liver function tests improved. After 4 weeks, a rechallenge was attempted with 37.5 mg venlafaxine PO daily; however, liver enzymes also increased with the lower dose. Health care providers should be vigilant for the possibility of drug-induced hepatitis in patients receiving venlafaxine.
[ Last revised: 1/18/2006 9:16:00 AM ]
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