Pharmacy & Therapeutics - April 2008 - (Page 233) Pharmaceutical Approval Update Mar vin M. Goldenberg, PhD, RPh, MS Desvenlafaxine (Pristiq) Manufacturer: Wyeth, Philadelphia, Pa. Indication: This product is indicated for the treatment of major depressive disorder (MDD) in adults. Drug Class: Pristiq is an extended-release, oral once-daily tablet that contains desvenlafaxine succinate, a structurally novel serotonin–norepinephrine reuptake inhibitor (SNRI). Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of Wyeth’s antidepressant venlafaxine (Effexor), which is used to treat MDD, generalized anxiety disorder, social anxiety disorder, and panic disorder. Venlafaxine XR was the first SNRI approved by the FDA for treating major depressive disorder. Uniqueness of Drug: Desvenlafaxine delivers the major active metabolite of venlafaxine HCl (Effexor XR) in its active state without going through the cytochrome P450 (CYP 2D6) metabolic pathway. This could be beneficial if desvenlafaxine is coadministered with other commonly prescribed medications that are metabolized through that pathway. The clinical efficacy of desvenlafaxine succinate is thought to be related to the potentiation of these neurotransmitters in the central nervous system (CNS). Black-Box Warning: Compared with placebo, antidepressants have been found to increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of MDD and other psychiatric disorders. Prescribers considering the use of desvenlafaxine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies have not shown an increase in the risk of suicidality with antidepressants, compared with placebo, in adults older than 24 years of age; there was a reduction in risk with antidepressants, compared with placebo, in adults 65 years of age and older. Depression and certain other psychiatric disorders are associated with increases in the risk of suicide. Patients of all ages who begin antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Desvenlafaxine is not approved for use in pediatric patients. Warnings and Precautions: Clinical worsening and suicide risk. Both adults and pediatric patients may experience worsening of their depression and/or the emergence of suicidal ideation and behavior or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. The author is President of Pharmaceutical and Scientific Services at MarvinMGoldenberg, LLC, in Westfield, N.J. His e-mail address is marvinmgoldenberg@verizon.net. 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 studies of antidepressants—the selective serotonin reuptake inhibitors (SSRIs) and others—showed that these drugs increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies have not shown an increase in the risk of suicidality with antidepressants, compared with placebo, in adults beyond age 24; there was a reduction with antidepressants, compared with placebo, in adults aged 65 and older. All patients using 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 either increases or decreases in dose. Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adults and pediatric patients being treated with antidepressants for MDD 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 the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Families and caregivers of patients being treated with antidepressants for MDD or other psychiatric and nonpsychiatric indications, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described here, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Serotonin syndrome. The development of a potentially life-threatening serotonin syndrome may occur with desvenlafaxine, particularly with the use of other serotonergic drugs (SSRIs, SNRIs, triptans) or with drugs that impair metabolism of serotonin, including monoamine oxidase inhibitors (MAOIs). Symptoms may include mental status changes (agitation, hallucinations, coma), autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (hyperreflexia, incoordination) or gastrointestinal (GI) symptoms (nausea, vomiting, diarrhea). The concomitant use of desvenlafaxine and MAOIs is contraindicated. If concomitant treatment with desvenlafaxine and an SSRI, another SNRI, or a 5-hydroxytr yptamine (5-HT) receptor agonist (triptan) is warranted, patients should be observed carefully, particularly during the beginning of treatment and with dose increases. The concomitant use of desvenlafaxine with serotonin precursors (tryptophan) is not recommended. Vol. 33 No. 4 • April 2008 • P&T® 233
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