Pharmacy & Therapeutics - April 2008 - (Page 196) only 100 mg and 150 mg Brief summary. See package insert for full prescribing information. Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to 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 LUVOX® CR (fluvoxamine maleate) Extended-Release Capsules or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies 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 risk with antidepressants compared to placebo in adults aged 65 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 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. LUVOX CR Capsules are not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS.) INDICATIONS—LUVOX CR (fluvoxamine maleate) Extended-Release Capsules are indicated for the treatment of social anxiety disorder (SAD), also known as social phobia, and for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) (both as defined in the DSM-IV). CONTRAINDICATIONS—Co-administration of alosetron, tizanidine, thioridazine, or pimozide; use of MAO inhibitors in combination with or within 14 days of discontinuing treatment with LUVOX CR; use in patients with a history of hypersensitivity to fluvoxamine maleate or any of the excipients. (See WARNINGS and PRECAUTIONS.) WARNINGS—Clinical Worsening and Suicide Risk: Adult and pediatric patients with MDD 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 antidepressants, 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. There has been a longstanding 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. The pooled analyses of shortterm placebo-controlled trials of antidepressants (SSRIs and others) showed that these drugs increased the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults ≥65 years. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, OCD, or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressants in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressants 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 1000 patients treated) include drug-related increases (14 additional cases in patients <18 years old; 5 in 18- to 24-year-olds) and decreases (1 fewer case in 25- to 64-year-olds; 6 fewer cases in patients ≥ 65 years old). No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials 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 (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 psychiatric and nonpsychiatric indications. 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with LUVOX CR). 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 above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Monitoring should include daily observation by families and caregivers. Prescriptions for LUVOX CR should be written for the smallest quantity of capsules consistent with good patient management 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 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. LUVOX CR is not approved for use in treating bipolar depression. Potential for Monoamine Oxidase Inhibitors (MAOIs) Interaction: In patients receiving another serotonin reuptake inhibitor drug in combination with MAOIs, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have discontinued that drug and have been started on an MAOI. Some cases presented with features resembling a serotonin syndrome or neuroleptic malignant syndrome. Therefore, LUVOX CR should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS). Potential Thioridazine Interaction: The effect of fluvoxamine (25 mg immediate-release [IR] given twice daily [bid] for 1 week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its 2 active metabolites, mesoridazine and sulforidazine, increased 3-fold following co-administration of fluvoxamine. Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This experience likely underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced at higher doses. Therefore, LUVOX CR and thioridazine should not be co-administered (see CONTRAINDICATIONS and PRECAUTIONS). Potential Tizanidine Interaction: Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of IR fluvoxamine maleate (100 mg daily for 4 days) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a single dose of tizanidine has been studied in 10 healthy male subjects. Tizanidine Cmax was increased ~12-fold (range 5- to 32-fold), elimination half-life was increased almost 3-fold, and AUC increased 33-fold (range 14- to 103-fold). The mean maximal effect
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