FDA label dfbd818b-8b54-4ea1-828d-b9b86c10000e

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 maprotiline 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. Maprotiline is not approved for use in pediatric patients. (See 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) with major depressive disorder (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 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 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 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 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 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for maprotiline 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 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 maprotiline is not approved for use in treating bipolar depression. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including maprotiline may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Seizures have been associated with the use of maprotiline. Most of the seizures have occurred in patients without a known history of seizures. However, in some of these cases, other confounding factors were present, including concomitant medications known to lower the seizure threshold, rapid escalation of the dosage of maprotiline, and dosage that exceeded the recommended therapeutic range. The incidence of direct reports is less than 1/10 of 1%. The risk of seizures may be increased when maprotiline is taken concomitantly with phenothiazines, when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline or when the recommended dosage of maprotiline hydrochloride is exceeded. While a cause and effect relationship has not been established, the risk of seizures in patients treated with maprotiline may be reduced by (1) initiating therapy at a low dosage, (2) maintaining the initial dosage for 2 weeks before raising it gradually in small increments as necessitated by the long half-life of maprotiline (average 51 hours), and (3) keeping the dosage at the minimally effective level during maintenance therapy. (See DOSAGE AND ADMINISTRATION .) Extreme caution should be used when this drug is given to: • patients with a history of myocardial infarction; • patients with a history or presence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes and tachycardia.

<table ID="_Refid_c860993a-b160-4651-afe1-378bf474e" width="100%"><caption>Table 1</caption><col width="13%"/><col width="87%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Age Range</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Drug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated</content></th></tr></thead><tbody><tr><td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Increases Compared to Placebo</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14 additional cases</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18 to 24</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 additional cases</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreases Compared to Placebo</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25 to 64</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 fewer case</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>&#x2265; 65</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6 fewer cases</paragraph></td></tr></tbody></table>

ADVERSE REACTIONS The following adverse reactions have been noted with maprotiline and are generally similar to those observed with tricyclic antidepressants. Cardiovascular: Rare occurrences of hypotension, hypertension, tachycardia, palpitation, arrhythmia, heart block, and syncope have been reported with maprotiline. Psychiatric: Nervousness (6%), anxiety (3%), insomnia (2%), and agitation (2%); rarely, confusional states (especially in the elderly), hallucinations, disorientation, delusions, restlessness, nightmares, hypomania, mania, exacerbation of psychosis, decrease in memory, and feelings of unreality. Neurological: Drowsiness (16%), dizziness (8%), tremor (3%), and, rarely, numbness, tingling, motor hyperactivity, akathisia, seizures, EEG alterations, tinnitus, extrapyramidal symptoms, ataxia, and dysarthria. Anticholinergic: Dry mouth (22%), constipation (6%), and blurred vision (4%); rarely, accommodation disturbances, mydriasis, urinary retention, and delayed micturition. Allergic: Rare instances of skin rash, petechiae, itching, photosensitization, edema, and drug fever. Gastrointestinal: Nausea (2%) and, rarely, vomiting, epigastric distress, diarrhea, bitter taste, abdominal cramps and dysphagia. Endocrine: Rare instances of increased or decreased libido, impotence, and elevation or depression of blood sugar levels. Other: Weakness and fatigue (4%) and headache (4%); rarely, altered liver function, jaundice, weight loss or gain, excessive perspiration, flushing, urinary frequency, increased salivation, nasal congestion and alopecia. Note: Although there have been only isolated reports of the following adverse reactions with maprotiline, its pharmacologic similarity to tricyclic antidepressants requires that each reaction be considered when administering maprotiline. — Bone marrow depression, including agranulocytosis, eosinophilia, purpura, and thrombocytopenia, myocardial infarction, stroke, peripheral neuropathy, sublingual adenitis, black tongue, stomatitis, paralytic ileus, gynecomastia in the male, breast enlargement and galactorrhea in the female, and testicular swelling. Postintroduction Reports Voluntary reports of adverse events temporally associated with maprotiline that have been received since market introduction and that may have no casual relationship with the drug include the following: interstitial pneumonitis which were in some cases associated with eosinophilia and increased liver enzymes, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.