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Special Warnings: Clinical worsening of depressive symptoms, unusual changes in behavior, and suicidality: Desvenlafaxine succinate is an SNRI, a class of medicines that may be used to treat depression. All patients treated with desvenlafaxine should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual change in behaviour. 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 depressed patients, and the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose.
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 (SSRIs and others) showed that these medicines increase the risk of suicidality in children, adolescents, and young adults (ages 18 to 24 years) with major depressive disorder (MDD) and other psychiatric disorders. Short-term trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older.
Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
Discontinuation effects: During marketing of serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), there have been post-marketing reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures, visual impairment, and hypertension. While these events are generally self-limited, there have been postmarketing reports of serious discontinuation symptoms, which can be protracted and severe. Completed suicide, suicidal thoughts, and severe aggression (including hostility, rage, and homicidal ideation) have been observed in patients during reduction in desvenlafaxine dosage, including during discontinuation.
Patients should be monitored when discontinuing treatment with desvenlafaxine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered (see DOSAGE & ADMINISTRATION AND ADVERSE REACTIONS). In some patients, discontinuation may need to occur over periods of 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.
Mania/Hypomania: In clinical trials, mania was reported for 0.03% of patients treated with desvenlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, desvenlafaxine should be used cautiously in patients with a history or family history of mania or hypomania (see ADVERSE REACTIONS).
Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions: As with other serotonergic agents, the development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions may occur with desvenlafaxine treatment, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs, amphetamines and triptans), with opioids, with drugs that impair metabolism of serotonin (e.g., MAOIs, including reversible MAOIs such as linezolid and intravenous methylene blue), or with antipsychotics or other dopamine antagonists (see DOSAGE & ADMINISTRATION and CONTRAINDICATIONS). Serotonin syndrome symptoms 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 desvenlafaxine 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 desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Narrow-angle glaucoma: Mydriasis has been reported in association with desvenlafaxine; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see ADVERSE REACTIONS).
Other information - Residual inert matrix tablet: Patients receiving desvenlafaxine succinate may notice an inert matrix tablet passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.
Precautions: Co-administration of drugs containing venlafaxine and/or desvenlafaxine: Desvenlafaxine is the major active metabolite of venlafaxine, a medication used to treat major depressive, generalized anxiety, social anxiety and panic disorders. Products containing desvenlafaxine succinate should not be used concomitantly with products containing venlafaxine hydrochloride or other products containing desvenlafaxine succinate.
Effects on blood pressure: Increases in blood pressure were observed in some patients in clinical trials, particularly with higher doses. Pre-existing hypertension should be controlled before treatment with desvenlafaxine. Patients receiving desvenlafaxine should have regular monitoring of blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving desvenlafaxine, either dose reduction or discontinuation should be considered. Caution should be exercised in treating patients with underlying conditions that might be compromised by increases in blood pressure (see ADVERSE REACTIONS).
Cardiovascular/cerebrovascular disorders: Caution is advised in administering desvenlafaxine to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders. Increases in blood pressure and heart rate were observed in clinical trials with desvenlafaxine. Desvenlafaxine has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical trials (see ADVERSE REACTIONS).
Serum lipids: Dose-related elevations in fasting serum total cholesterol, LDL (Low Density Lipoprotein) cholesterol, and triglycerides were observed in clinical trials. Measurement of serum lipids should be considered during treatment with desvenlafaxine (see ADVERSE REACTIONS).
Seizures: Cases of seizure were reported in clinical trials with desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical trials. Desvenlafaxine should be prescribed with caution in patients with a seizure disorder (see ADVERSE REACTIONS).
Abnormal bleeding: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including desvenlafaxine, may increase risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening haemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of desvenlafaxine and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
Hyponatremia: Cases of hyponatremia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion have been described with SNRIs (including desvenlafaxine succinate) and SSRIs, usually in volume-depleted or dehydrated patients, including elderly patients and patients taking diuretics (see ADVERSE REACTIONS).
Abuse and dependence: Physical and psychological dependence: Although desvenlafaxine has not been systematically studied in preclinical or clinical trials for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical trials.
Effects on ability to drive and use machines: Interference with cognitive and motor performance: The results of a clinical trial that assessed the effects of desvenlafaxine on behavioral performance of healthy individuals revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any CNS-active drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that desvenlafaxine therapy does not adversely affect their ability to engage in such activities.
