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Suicide/Suicidal Thoughts or Clinical Worsening: All patients treated with venlafaxine should be monitored appropriately and observed closely for clinical worsening and suicidality. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered, especially in patients with depression, and the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose (see Adverse Reactions).
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are strong predictors of suicide. Pooled analyses of short-term placebo-controlled trials of antidepressant medicines (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these medicines increase the risk of suicidality in children, adolescents, and young adults (ages 18-24 years) with major depression and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults older than 24 years of age; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older.
Aggression: Aggression may occur in some patients who have received antidepressants, including venlafaxine treatment, dose reduction, or discontinuation. As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.
Discontinuation: Discontinuation effects are well known to occur with antidepressants, and sometimes these effects can be protracted and severe (see Adverse Reactions). Suicide/suicidal thoughts and aggression have been observed in patients during changes in venlafaxine dosing regimen, including during discontinuation (see Suicide/Suicidal Thoughts or Clinical Worsening and Aggression as previously mentioned). It is therefore recommended that the dosage of venlafaxine be tapered gradually and individually and the patients be closely monitored during discontinuation (see Dosage & Administration). In some patients, discontinuation could take months or longer.
Sexual Dysfunction: Serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see Adverse Reactions). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs.
Bone Fractures: Epidemiological studies show an increased risk of bone fractures in patients receiving serotonin reuptake inhibitors (SRIs) including venlafaxine. The mechanism leading to this risk is not fully understood.
NMS-like Reactions: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition or NMS like reactions may occur with venlafaxine treatment, particularly with concomitant use of other serotonergic drugs including SSRIs, SNRIs, amphetamines, and triptans, fentanyl, dextromethorphan, tramadol, tapentadol, meperidine, methadone, pentazocine, with drugs that impair metabolism of serotonin including MAOIs, e.g., methylene blue, or with antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes (see Interactions).
If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of venlafaxine with serotonin precursors such as tryptophan supplements is not recommended.
Angle Closure Glaucoma: Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intra-ocular pressure or patients at risk for acute narrow angle glaucoma (angle closure glaucoma) be closely monitored.
Cardiovascular System: Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.
Dose-related increases in blood pressure have been reported in some patients treated with venlafaxine. Cases of elevated blood pressure requiring immediate treatment have been reported in post-marketing experience. Measurement of blood pressure is recommended for patients receiving venlafaxine. Pre-existing hypertension should be controlled before treatment with venlafaxine. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure.
Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.
Cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia, and sudden death have been reported during the post-marketing use of venlafaxine. The majority of reports occurred in association with overdose or in patients with other risk factors for QTc prolongation/TdP. Therefore, venlafaxine should be used with caution in patients with risk factors for QTc prolongation.
Convulsions: Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be introduced with caution in patients with a history of convulsions.
Mania/Hypomania: Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.
Hyponatremia: Cases of hyponatremia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion may occur with venlafaxine, usually in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume depleted, may be at greater risk for this event.
Bleeding: Drugs that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. There have been reports of bleeding abnormalities with venlafaxine ranging from skin and mucous membrane bleeding and gastrointestinal hemorrhage, to life-threatening hemorrhage. As with other SRIs, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors.
Weight Loss: The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine hydrochloride and weight loss agents is not recommended. Venlafaxine hydrochloride is not indicated for weight loss, alone or in combination with other products.
Serum Cholesterol: Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.
Abuse and Dependence: Clinical studies did not show evidence of drug-seeking behavior, development of tolerance, or dose escalation over time.
In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant central nervous system (CNS) stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. In a self-administration study, rhesus monkeys have been shown to self-administer venlafaxine intravenously.
Other Information: The extended-release formulation of venlafaxine contains spheroids, which release the drug slowly into the digestive tract. The insoluble portion of these spheroids is eliminated and may be seen in stools.
Effects on Ability to Drive and Use Machines: Venlafaxine did not affect psychomotor, cognitive or complex behavior performance in healthy volunteers. However, any psychoactive drug may impair judgment, thinking, and motor skills. Therefore, patients should be cautioned about their ability to drive or operate hazardous machinery.
Use in Children and Adolescents: Efficacy in patients younger than 18 years of age has not been established.
Regular measurement of weight and blood pressure is recommended if venlafaxine is used in children and adolescents. Discontinuation of venlafaxine treatment should be considered in children and adolescents who experience a sustained increase in blood pressure. Measurement of serum cholesterol levels should be considered during long term treatment of children and adolescents (see Use in Children and Adolescent under Dosage & Administration and Adverse Reactions). Safety in children younger than 6 years of age has not been evaluated.
