Sign Out
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. 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 18-24) with major depression 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 age 24; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults aged 65 years and older.
The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageNo suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and non-psychiatric. 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 suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Discontinuation of Treatment with PRISTIQ as follows and Discontinuing PRISTIQ under Dosage & Administration for a description of the risks of discontinuation of PRISTIQ].
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PRISTIQ should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening patients for bipolar disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described previously represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that PRISTIQ is not approved for use in treating bipolar depression.
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 PRISTIQ treatment, particularly with concomitant use of other serotonergic drugs [including SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids (e.g., fentanyl, tramadol), lithium, tryptophan, buspirone, amphetamines, and St. John's Wort], 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.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing and hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures 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. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of PRISTIQ with MAOIs intended to treat psychiatric disorders is contraindicated. PRISTIQ should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking PRISTIQ. PRISTIQ should be discontinued before initiating treatment with the MAOI [see Monoamine Oxidase Inhibitors under Contraindications and Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders under Dosage & Administration].
If concomitant treatment with PRISTIQ and other serotonergic drugs, including triptans, tricyclic antidepressants, opioids (e.g., fentanyl, tramadol), lithium, buspirone, amphetamines, tryptophan and St. John's Wort, that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, and the patient should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
The concomitant use of PRISTIQ with serotonin precursors (such as tryptophan) is not recommended.
Treatment with PRISTIQ and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the events as previously mentioned occur and supportive symptomatic treatment should be initiated.
Elevated Blood Pressure: Patients receiving PRISTIQ should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies, particularly with higher doses. Pre-existing hypertension should be controlled before initiating treatment with PRISTIQ. Caution should be exercised in treating patients with underlying conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with PRISTIQ.
Sustained hypertension: Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving PRISTIQ, either dose reduction or discontinuation should be considered [see Clinical Trials Experience under Adverse Reactions]. Treatment with PRISTIQ at all doses from 50 mg/day to 400 mg/day in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 2). Analyses of patients in PRISTIQ controlled studies who met criteria for sustained hypertension revealed a consistent increase in the proportion of patients who developed sustained hypertension. This was seen at all doses with a suggestion of a higher rate at 400 mg/day. (See Table 2.)
Click on icon to see table/diagram/imageAbnormal Bleeding: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including PRISTIQ, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of PRISTIQ and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
Narrow-angle Glaucoma: Mydriasis has been reported in association with PRISTIQ; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored.
Activation of Mania/Hypomania: In clinical trials, mania was reported for 0.03% of patients treated with PRISTIQ. 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, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania.
Cardiovascular/Cerebrovascular Disorders: Caution is advised in administering PRISTIQ to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders [see Clinical Trials Experience under Adverse Reactions]. Increases in blood pressure and small increases in heart rate were observed in clinical studies with PRISTIQ. PRISTIQ 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 studies.
Serum Cholesterol and Triglyceride Elevation: Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in the controlled studies. Measurement of serum lipids should be considered during treatment with PRISTIQ [see Clinical Trials Experience under Adverse Reactions].
Discontinuation of Treatment with PRISTIQ: Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with PRISTIQ during clinical studies in MDD. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy.
During marketing of SNRIs and 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., paresthesia, 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-limiting, there have been reports of serious discontinuation symptoms, and sometimes these effects can be protracted and severe. In addition, suicide/suicidal thoughts and aggression have been observed in patients during changes in desvenlafaxine dosing regimen, including during discontinuation.
Patients should be monitored when discontinuing treatment with PRISTIQ. 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 Discontinuing PRISTIQ under Dosage & Administration and Clinical Trials Experience under Adverse Reactions]. In some patients, discontinuation may need to occur over periods of months or longer.
Seizures: Cases of seizure have been reported in clinical trials with PRISTIQ. PRISTIQ has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical trials. PRISTIQ should be prescribed with caution in patients with a seizure disorder.
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ. In many cases, this hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk [see Use in the Elderly under Precautions and Pharmacology: Pharmacokinetics: Special Populations under Actions]. Discontinuation of PRISTIQ should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
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.
Interstitial Lung Disease and Eosinophilic Pneumonia: Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with PRISTIQ who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of PRISTIQ should be considered.
Sexual Dysfunction: Serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction [see Clinical Trials Experience under Adverse Reactions]. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs.
Renal Impairment: In patients with moderate or severe renal impairment or end-stage renal disease (ESRD) the clearance of PRISTIQ was decreased, thus prolonging the elimination half-life of the drug. As a result, there were potentially clinically significant increases in exposures to PRISTIQ [see Pharmacology: Pharmacokinetics: Special Populations under Actions]. Dosage adjustment (50 mg every other day) is necessary in patients with severe renal impairment or ESRD. The doses should not be escalated in patients with moderate or severe renal impairment or ESRD [see Special Populations under Dosage & Administration].
In subjects with renal impairment the clearance of PRISTIQ was decreased. In subjects with severe renal impairment (24-hr CrCl <30 mL/min) and end-stage renal disease, elimination half-lives were significantly prolonged, increasing exposures to PRISTIQ; therefore, dosage adjustment is recommended in these patients [see Special Populations under Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations under Actions].
Hepatic Impairment: The mean t1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50 mg/day.
Dose escalation above 100 mg/day is not recommended [see Pharmacology: Pharmacokinetics: Special Populations under Actions].
ABUSE AND DEPENDENCE: Controlled Substance: Desvenlafaxine is not a controlled substance.
Abuse and Dependence: Although PRISTIQ has not been systematically studied in preclinical or clinical studies for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical studies. However, it is not possible to predict on the basis of pre-marketing experience, the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PRISTIQ (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
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.
Use in Children: Two placebo-controlled studies in 587 pediatric patients 7 to 17 years of age with MDD did not demonstrate efficacy. Anyone considering the use of PRISTIQ in a child or adolescent must balance the potential risks with the clinical need.
In general, the adverse reaction profile of PRISTIQ (in placebo-controlled clinical studies) in children and adolescents (aged 7 to 17) was similar to that seen for adults.
The most frequently reported events from the placebo-controlled studies were: Headache (17.3%), Nausea (8.6%), Abdominal pain upper (8.5%), Nasopharyngitis (5.3%), Dizziness (4.6%), Upper respiratory tract infection (4.2%), Decreased appetite (4.2%), Vomiting (3.9%), Fatigue (3.2%), and Insomnia (3.2%). Of these, events with an incidence in the PRISTIQ groups >2 times that of the placebo group were: Fatigue (4.2% vs. 1.7%), and Insomnia (4.2% vs. 1.7%).
When compared to adverse event rates in adults, the following events occurred more frequently in pediatric patients (incidence of ≥3% in pediatric patients and <3% in adults): Abdominal pain upper, Weight increased, Gastroenteritis viral, Dysmenorrhoea, Accidental overdose, Cough, Irritability, Oropharyngeal pain, and Sinusitis.
As with adults, increased blood pressure, abnormal bleeding, mania/hypomania, discontinuation syndrome, seizure, suicide attempt, suicidal behavior, self-injurious behavior and suicidal ideation were observed in pediatric clinical studies (see Clinical Worsening of Depressive Symptoms, Unusual Changes in Behavior, and Suicidality under Precautions).
Use in the Elderly: Of the 7,785 patients in MDD clinical studies with PRISTIQ, approximately 5% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term, placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with PRISTIQ [see Adverse Reactions]. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see Special Populations under Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations under Actions]. If PRISTIQ is poorly tolerated, every other day dosing can be considered.
SSRIs and SNRIs, including PRISTIQ, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Hyponatremia as previously mentioned].
Greater sensitivity of some older individuals cannot be ruled out.
