"The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.
Major depressive disorder (MDD), commonly referred to as depression, is a mental disorder characterized by mo"...
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Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, ie, beyond several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be 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. Such observation would generally include at least weekly face-toface contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, 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 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 suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for DESYREL (trazodone hydrochloride) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.
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 trials) 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 above 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 DESYREL (trazodone hydrochloride) is not approved for use in treating bipolar depression.
TRAZODONE HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF PRIAPISM. IN MANY OF THE CASES REPORTED, SURGICAL INTERVENTION WAS REQUIRED AND, IN A SOME OF THESE CASES, PERMANENT IMPAIRMENT OF ERECTILE FUNCTION OR IMPOTENCE RESULTED. MALE PATIENTS WITH PROLONGED OR INAPPROPRIATE ERECTIONS SHOULD IMMEDIATELY DISCONTINUE THE DRUG AND CONSULT THEIR PHYSICIAN.
The detumescence of priapism and drug-induced penile erections has been accomplished by both pharmacologic, eg, the intracavernosal injection of alpha-adrenergic stimulants such as epinephrine and norepinephrine, as well as surgical procedures.2-7 Any pharmacologic or surgical procedure utilized in the treatment of priapism should be performed under the supervision of a urologist or a physician familiar with the procedure and should not be initiated without urologic consultation if the priapism has persisted for more than 24 hours.
DESYREL (trazodone hydrochloride) is not recommended for use during the initial recovery phase of myocardial infarction.
Caution should be used when administering DESYREL (trazodone hydrochloride) to patients with cardiac disease, and such patients should be closely monitored, since antidepressant drugs (including DESYREL (trazodone hydrochloride) ) have been associated with the occurrence of cardiac arrhythmias. Recent clinical studies in patients with pre-existing cardiac disease indicate that DESYREL (trazodone hydrochloride) may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, and in two patients, short episodes (3–4 beats) of ventricular tachycardia.
The possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Therefore, prescriptions should be written for the smallest number of tablets consistent with good patient management.
Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving DESYREL (trazodone hydrochloride) . Concomitant administration of antihypertensive therapy with DESYREL (trazodone hydrochloride) may require a reduction in the dose of the antihypertensive drug.
Little is known about the interaction between DESYREL (trazodone hydrochloride) and general anesthetics; therefore, prior to elective surgery, DESYREL (trazodone hydrochloride) should be discontinued for as long as clinically feasible.
As with all antidepressants, the use of DESYREL (trazodone hydrochloride) should be based on the consideration of the physician that the expected benefits of therapy outweigh potential risk factors.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with DESYREL (trazodone hydrochloride) and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for DESYREL (trazodone hydrochloride) . The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking DESYREL (trazodone hydrochloride) .
Clinical Worsening and Suicide Risk
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 early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-today basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Because priapism has been reported to occur in patients receiving DESYREL (trazodone hydrochloride) , patients with prolonged or inappropriate penile erection should immediately discontinue the drug and consult with the physician (see WARNINGS).
Antidepressants may impair the mental and/or physical ability required for the performance of potentially hazardous tasks, such as operating an automobile or machinery; the patient should be cautioned accordingly.
DESYREL (trazodone hydrochloride) may enhance the response to alcohol, barbiturates, and other CNS depressants.
DESYREL (trazodone hydrochloride) should be given shortly after a meal or light snack. Within any individual patient, total drug absorption may be up to 20% higher when the drug is taken with food rather than on an empty stomach. The risk of dizziness/lightheadedness may increase under fasting conditions.
Occasional low white blood cell and neutrophil counts have been noted in patients receiving DESYREL (trazodone hydrochloride) . These were not considered clinically significant and did not necessitate discontinuation of the drug; however, the drug should be discontinued in any patient whose white blood cell count or absolute neutrophil count falls below normal levels. White blood cell and differential counts are recommended for patients who develop fever and sore throat (or other signs of infection) during therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving DESYREL (trazodone hydrochloride) in daily oral doses up to 300 mg/kg for 18 months.
Pregnancy Category C
DESYREL (trazodone hydrochloride) has been shown to cause increased fetal resorption and other adverse effects on the fetus in two studies using the rat when given at dose levels approximately 30 to 50 times the proposed maximum human dose. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15 to 50 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. DESYREL (trazodone hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
DESYREL (trazodone hydrochloride) and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when DESYREL (trazodone hydrochloride) is administered to a nursing woman.
Anyone considering the use of DESYREL (trazodone hydrochloride) in a child or adolescent must balance the potential risks with the clinical need.
2. Lue TF, Physiology of erection and pathophysiology of impotence. In: Wash PC, Retik AB, Stamey TA, Vaughan ED, eds. Campbell's Urology. Sixth edition. Philadelphia: W.B. Saunders; 1992: 722-725.
3. Goldstein I, Krane RJ, Diagnosis and therapy of erectile dysfunction. In: Wash PC, Retik AB, Stamey TA, Vaughan ED, eds. Campbell's Urology. Sixth edition. Philadelphia: W.B. Saunders; 1992: 3071-3072.
4. Yealy DM, Hogya PT: Priapism. Emerg Med Clin North Am. 1988; 6:509-520.
5. Banos JE, Bosch F, Farre M, Drug-induced priapism. Its aetiology, incidence and treatment. Med Toxicol Adverse Drug Exp. 1989; 4:46-58.
6. O'Brien WM, O'Connor KP, Lynch JH. Priapism: current concepts. Ann Emerg Med. 1989: 980-983.
7. Bardin ED, Krieger JN. Pharmacological priapism: comparison of trazodone- and papaverine-associated cases. Int Urol Nephrol . 1990; 22:147-152.
Last reviewed on RxList: 4/13/2011
This monograph has been modified to include the generic and brand name in many instances.
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