Pharmacy & Therapeutics - March 2009 - (Page 157) Pharmaceutical Approval Update Mar vin M. Goldenberg, PhD, RPh, MS Milnacipran HCl (Savella) Film-Coated Tablets for Fibromyalgia Manufacturer: Forest Laboratories, New York/ Cypress Biosciences, Inc., San Diego Indication: Milnacipran is indicated for the management of fibromyalgia. It is not approved for use in pediatric patients. Drug Class: The drug acts like medications that are used to treat depression and other psychiatric disorders. Milnacipran is a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI). Its chemical formula is (1R,2S)-rel-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide HCl. Its molecular weight is 282.8 daltons. Uniqueness of Drug: As a member of the SNRI class, milnacipran is used in Europe and Asia to relieve symptoms of depression. However, it has also been effective in relieving the chronic pain associated with several types of illnesses, including fibromyalgia. By blocking the reuptake of neurotransmitters NE and 5-HT (two of the primary hormones that are involved in depression and sensations of severe and chronic pain), more neurotransmitters are left in the synaptic cleft for a greater effect on the neurons in the hippocampus to control mood and pain sensation. Boxed Warning: Suicidality and antidepressant drugs. Milnacipran is a SNRI, similar to some drugs used to treat depression and other psychiatric disorders. Antidepressants increased the risk, compared with placebo, of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies have not shown an increased risk of suicidality with antidepressants compared with placebo in adults beyond age 24, and 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 themselves associated with increases in the risk of suicide. Patients of all ages who are started on milnacipran 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 obser vation and communication with the prescriber. Milnacipran is not approved for use in the treatment of MDD or for use in pediatric patients. Warnings and Precautions: Suicide risk. Milnacipran is similar to some drugs used for the treatment of depression and other psychiatric disorders. Patients, both adult and pediatric, with depression or other psyThe author is President of Pharmaceutical and Scientific Services at Marvin M. Goldenberg, LLC, in Westfield, N.J. His e-mail address is marvinmgoldenberg@verizon.net. chiatric disorders may experience worsening of their depression and/or the emergence of suicidality or unusual changes in behavior, whether or not they are taking these medications. 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. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of NE and/or 5-HT, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. In placebo-controlled clinical trials of adults with fibromyalgia, among patients who had a history of depression at the start of treatment, the incidence of suicidal ideation was 0.5% with placebo, 0% with milnacipran 100 mg/day, and 1.3% with milnacipran 200 mg/day. No suicides occurred in the shortterm or longer-term (up to one year) fibromyalgia trials. 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 of differences (drug versus placebo), however, was relatively stable within age strata and for all indications. 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 drugs inhibiting the reuptake of NE and/or 5-HT 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 or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Changing the therapeutic regimen, including discontinuing the medication, might be considered if patients are experiencing worsening depressive symptoms or are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset or were not part of the patient’s presenting symptoms. If treatment is discontinued because of worsening depressive symptoms or emergent suicidality, the medication should be tapered as rapidly as feasible. It should be recognized, however, that abrupt discontinuation can produce withdrawal symptoms. Serotonin syndrome. The development of a potentially lifethreatening serotonin syndrome may occur with agents that inhibit serotonin reuptake, including milnacipran, particularly with the concomitant use of serotonergic drugs, including triptans and tramadol (Ultram, Ortho-McNeil), and with drugs Vol. 34 No. 3 • March 2009 • P&T® 157
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