FDA label 3e01fc3b-dffa-314b-e054-00144ff88e88

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placbo 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 mirtazapine tablets 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 antidepressant 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. Patiets 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. Mirtazapine is not approved for use in pediatric patients. WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS: Information for Patients , and PRECAUTIONS: Pediatric Use )

WARNINGS 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. 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 drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) within major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antideressants 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. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 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 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 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) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case 6 fewer cases 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 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 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, 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 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 Mirtazapine tablets 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 initial presentation of bipolar disorders. it is generally believed (though not established in controlled trials) tha treating such an epidose 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 decribed 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 mirtazapine tablets are not approved for use in treating bipolar depression. Agranulocytosis In premarketing clinical trials, 2 (1 with SjSyndrome) out of 2,796 patients treated with mirtazapine tablets developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after mirtazapine was stopped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval i.e., 2.2 cases per 10,000 to 3.1 cases per 1,000. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with mirtazapine should be discontinued and the patient should be closely monitored. MAO Inhibitors In patients receiving other drugs for major depressive disorder in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued a drug for major depressive disorder and then are started on an MAOI, there have been reports of serious and sometimes fatal, reactions, including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with mirtazapine tablets, it is recommended that mirtazapine not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SSRIs, SNRIs, MAOIs, and other serotonergic drugs used as monotherapy, including mirtazapine tablets, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, 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 mirtazapine tablets with MAOIs intended to treat depression is contraindicated [see CONTRAINDICATIONS]. If concomitant treatment of mirtazapine tablets with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of mirtazapine tablets with serotonin precursors (such as tryptophan) is not recommended. Treatment with mirtazapine tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

ADVERSE REACTIONS Associated with Discontinuation of Treatment Approximately 16 % of the 453 patients who received mirtazapine tablets in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7 % of the 361 placebo-treated patients in those studies. The most common events (1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2: Table 2: Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US Mirtazapine Trials Adverse Event Percentage of Patients Discontinuing with Adverse Event Mirtazapine (n=453) Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0% Commonly Observed Adverse Events in US Controlled Clinical Trials The most commonly observed adverse events associated with the use of mirtazapine tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (mirtazapine incidence at least twice that for placebo) are listed in Table 3: Table 3: Common TreatmentAdverse Events Associated with the Use of Mirtazapine in 6-Week US Trials Adverse Event Percentage of Patients Reporting Adverse Event Mirtazapine (n=453) Placebo (n=361) Somnolence 54% 18% Increased Appetite 17% Weight Gain 12% 2% Dizziness 7% 3% Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine-Treated Patients Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among mirtazapine tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied. Table 4: Incidence of Adverse Clinical Experiences1 (In Short-Term U.S. Controlled Studies Body System Adverse Clinical Experience Mirtazapine (n=453) Placebo (n=361) 1Events reported by at least 1% of patients treated with mirtazapine are included, except the following events which had an incidence on placebo grater than or equal to mirtazapine: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnolence 54% 18% Dizziness 7% 3% Abnormal Dreams 4% 1% Thinking Abnormal 3% 1% Tremor 2% 1% Confusion 2% 0% Respiratory System Dyspnea 1% 0% Urogenital System Urinary Frequency 2% 1% ECG Changes The electrocardiograms for 338 patients who received mirtazapine tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTcmsec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine During its premarketing assessment, multiple doses of mirtazapine tablets were administered to 2,796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2,796 patients exposed to multiple doses of mirtazapine who experienced an event of the type cited on at least 1 occasion while receiving mirtazapine. All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote. It is important to emphasize that, although the events reported occurred during treatment with mirtazapine, they were not necessarily caused by it. WARNINGSand PRECAUTIONSsections. Events are further categorized by body system and listed in order of decreasing frequent according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in Table 4 appear in this listing. Events of major clinical impotance are also described in the WARNINGS and PRECAUTIONS sections. Body as a Whole: frequent:malaise, abdominal pain, abdominal syndrome acute; infrequent:chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, adomen enlarged; rare: cellulitis, chest pain substernal. Cardiovascular System: frequent:hypertension, vasodilatation; infrequent;angina pectois, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension;rare:atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. Digestive System: frequent:vomiting, anorexia;infrequent:eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. Endocrine System:rare: goiter, hypothyroidism. Hemic and Lymphatic System:rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. Metabolic and Nutritional Disorders: frequent:thirst; infrequent:dehydration, weight loss; rare:gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes melllitus, hyponatremia. Musculoskeletal System: frequent:myasthenia, arthralgia; infrequent: arthritis, tenosynovitis;rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. Nervous System: frequent:hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitatiom, anxiety, amnesia, hyperkinesia, paresthesia; infrequent:ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneuomnia; rare:asphyxia, laryngitis, pneumothorax, hiccup. Skin and Appendages: frequent: oruritus, rash;infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. Special Senses: infrequent:eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare:blepharitis, parital transitory deafness, otitis media, taste loss, parosmia. Urogenital System: frequent: urinary tract infection; infrequent:kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence;rare:polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargment, urinary urgency. Other Adverse Events Observed During Postmarketing Evaluation of Mirtazapine Adverse events reported since market introduction, which were temporally (but not necessarily casually) related to mirtazapine therapy, include 4 cases of the ventricular arrhythmia torsades de pointes. In 3 of the 4 cases, however, concomitant drugs were implicated. All patients recovered. Cases of severe skin reactions, including Stevens-Johnson Syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported.